new born pharmacokinetics

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Advanced Drug Delivery Reviews 55 (2003) 667686www.elsevier.com/locate/addr

Pharmacokinetics in the newborna , b*Jane Alcorn , Patrick J. McNamara

aCollege of Pharmacy and Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK, S7N 5C9, Canada

bDivision of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536, USA

Received 11 June 2002; accepted 22 January 2003

Abstract

In addition to differences in the pharmacodynamic response in the infant, the dose and the pharmacokinetic processes

acting upon that dose principally determine the efficacy and/or safety of a therapeutic or inadvertent exposure. At a given

dose, significant differences in therapeutic efficacy and toxicant susceptibility exist between the newborn and adult.

Immature pharmacokinetic processes in the newborn predominantly explain such differences. With infant development, the

physiological and biochemical processes that govern absorption, distribution, metabolism, and excretion undergo significant

growth and maturational changes. Therefore, any assessment of the safety associated with an exposure must consider the

impact of these maturational changes on drug pharmacokinetics and response in the developing infant. This paper reviews

the current data concerning the growth and maturation of the physiological and biochemical factors governing absorption,

distribution, metabolism, and excretion. The review also provides some insight into how these developmental changes alter

the efficiency of pharmacokinetics in the infant. Such information may help clarify why dynamic changes in therapeutic

efficacy and toxicant susceptibility occur through infancy.

2003 Elsevier Science B.V. All rights reserved.

Keywords: Development; Exposure; Human; Infant; Newborn; Pharmacokinetics

Contents

1. Introduction ............................................................................................................................................................................ 668

1.1. Pharmacokinetics as a determinant of plasma concentration and response........................ ................... .................... .............. 668

2. Absorption................... ................... .................... .................... .................... ................... .................... .................... ................. 669

2.1. Gastrointestinal absorption......................... .................... ................... .................... .................... .................... ................... . 669

2.1.1. Gastrointestinal secretions................................ .................... .................... ................... .................... .................... .... 6702.1.2. Gastrointestinal motility.......................... ................... .................... .................... ................... .................... .............. 670

2.1.3. Gastrointestinal metabolism and transport ................... .................... .................... ................... .................... .............. 671

2.2. Gastrointestinal first-pass effects ................... .................... .................... ................... .................... .................... ................. 671

3. Distribution........................ .................... .................... .................... ................... .................... .................... ................... ........... 672

3.1. Body composition and tissue perfusion .................... .................... ................... .................... .................... .................... ....... 672

3.2. Plasma protein binding .................... .................... .................... ................... .................... .................... ................... ........... 673

4. Elimination.................. ................... .................... .................... .................... ................... .................... .................... ................. 673

*Corresponding author. Tel.: 11-306-966-6365; fax: 11-306-966-6377.

E-mail address: [email protected] (J. Alcorn).

0169-409X/03/$ see front matter 2003 Elsevier Science B.V. All rights reserved.

doi:10.1016/S0169-409X(03)00030-9
mailto:[email protected]:[email protected]:[email protected]:[email protected]:[email protected]


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668 J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686

4.1. Hepatic clearance............ ................... .................... .................... ................... .................... .................... .................... ....... 674

4.1.1. Intrinsic clearance ................. .................... .................... ................... .................... .................... ................... ........... 674

4.1.1.1. Cytochrome P450 enzyme-mediated metabolism ................... .................... .................... ................... ........... 674

4.1.1.2. Phase II metabolism............... .................... .................... ................... .................... .................... ................. 676

4.1.1.3. Consequences of variability in the postnatal maturation of phase I and phase II reactions............... ................. 678

4.1.2. Hepatic first-pass effects .................. .................... ................... .................... .................... ................... .................... . 6784.2. Renal clearance..... ................... .................... .................... .................... ................... .................... .................... ................. 678

4.2.1. Glomerular filtration.............. .................... .................... ................... .................... .................... ................... ........... 679

4.2.2. Renal tubular function .................. ................... .................... .................... ................... .................... .................... .... 679

5. Conclusions ............................................................................................................................................................................ 680

References ................... .................... .................... .................... ................... .................... .................... ................... .................... . 680

1. Introduction affects of postnatal development on drug and toxic-

ant pharmacokinetics in the newborn and early

Adult doses, even after adjusted for differences in infancy. The article describes the age-dependent

body weight, often lead to drastic consequences in changes in the physiological and/or biochemical

the newborn patient. Functional immaturity of phys- processes governing drug and toxicant phar-

iological processes and organ function predispose macokinetics. The article then extends these observa-

newborns to exhibit such disparate responses relative tions to discuss how developmental changes may

to the adult. With infant maturation, normal develop- lead to significant differences in absorption, dis-

ment may modify infant response to drug and tribution, metabolism and/or excretion between the

toxicant exposures. The full impact of developmental newborn, infant and the adult. Such discussion

immaturity, though, still remains unrealized as ex- should help explain the dynamic changes in thera-

emplified by the number of well-documented therapeutic efficacy and toxicant susceptibility that occur

peutic misjudgments that continue even to this day through infancy.

[13]. We may mitigate future misjudgments through

a greater understanding of how development affects 1.1. Pharmacokinetics as a determinant of plasma

the factors that govern drug and toxicant response in concentration and responsethe newborn and young infant. Such knowledge may

help ensure safe exposures to therapeutic or inadver- Therapeutic and toxic responses generally corre-

tent compounds. late well with the plasma concentration of a com-

Pharmacokinetic and pharmacodynamic processes pound. Because of this correlation, plasma concen-

contribute to the significant differences in therapeutic trations may best indicate the potential safety and/or

efficacy and toxicant susceptibility observed between efficacy of the compound in the newborn and young

newborns, young infants and adults. With postnatal infant. This presumes that the pharmacological or

development, growth and functional maturation of toxic response is direct (i.e., related to corresponding

the biochemical and physiological factors governing serum concentrations), expected (i.e., similar to adult

pharmacokinetics may alter the processes of absorp- response) and quantitatively similar to adults (i.e.,

tion, distribution, metabolism and excretion. As well, similar pharmacodynamic parameters). A more dif-these developmental changes proceed along a con- ficult situation arises if the pharmacological or toxic

tinuum, at different rates and patterns, resulting in response is indirect (i.e., unrelated to serum con-

tremendous interindividual variability in infant phar- centrations), novel (a function of the developing

macokinetics. The dynamic and highly variable neonatal physiology/biochemistry) and quantitative-

character of postnatal maturation of infant phar- ly dissimilar to adults. Whether pharmacodynamic

macokinetic and pharmacodynamic processes may differences exist between pediatric population groups

have significant consequences on the way newborns and adults is largely unknown. Given this presump-

and infants respond to and deal with drugs. tion, two factors govern plasma concentrations, the

As its principal goal, this review discusses the size of the dose and the pharmacokinetic processes


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J. Alcorn, P.J. McNamara / Advanced Drug Delivery Reviews 55 (2003) 667686 669

of absorption, distribution, metabolism and excretion exhibit differences in toxicant susceptibility or thera-

acting upon that dose. The following equations peutic efficacy.

illustrate the influence of dose and pharmacokinetic In general, the combined effects of maturation of

processes on plasma concentrations of a compound, each pharmacokinetic process on the plasma levels

administered as either a multiple oral dose (Eq. (1)) of a given compound are not well understood.or as a single oral dose (Eq. (2)). Premature birth (gestational age ,36 weeks) and

underlying pathophysiology further complicate theFD relationship between plasma concentrations and re-]

t sponse and the age-related changes in phar-]]C5 (multiple dose) (1)Cl

S macokinetics. Premature infants exhibit more pro-

nounced anatomical and functional immaturity of theor organs involved in pharmacokinetic processes. The

extent to which premature infants differ from theCl SFk D

a ]2 t 2 k tS D s da full-term infant correlates directly with the degree ofV]]]S DC5 e 2 e (single dose)dt V k 2 ks dd a e prematurity [4]. This enhanced immaturity, as wellas any underlying disease state(s), may impede

(2) normal postnatal development of the processes of absorption, distribution and elimination. How thesewhere C is the average steady state plasma con-

and other factors may contribute to age-dependentcentration; F is the bioavailability; D is the dose; tpharmacokinetics in newborns and infants requiresis the dosing interval; Cl is the systemic clearance;

S

consideration. The proceeding discussion will sum-C is the plasma concentration at any time, t; k ist a

marize the available literature on the influence ofthe absorption rate constant; k is the elimination ratee

postnatal maturation on drug absorption, distribution,constant and is equal to Cl /V ; V is the volume ofS d dmetabolism and excretion principally in the full-termdistribution; and t is time.infant.According to Eqs. (1) and (2), larger doses (D)

result in higher plasma concentrations of an adminis-

tered compound. As well, these equations clearly

2. Absorptionillustrate the importance of absorption (indicated inthe F and k terms), distribution (indicated in the V

a d

Age-related differences in absorption relate toterm), and metabolism and excretion (indicated indevelopmental changes in those factors governingthe Cl and k terms) as determinants of plasmaS epassive or carrier-mediated transport across theconcentrations in the newborn and young infant.absorptive barrier. Systemic bioavailability becomesRapid changes in body size and composition, organan important consideration when compounds aresize and function, and maturation of the underlyingabsorbed from extravascular administration sites.physiological and biochemical processes that governThe absorptive characteristics of the compound andabsorption, distribution, metabolism, and excretionthe possible influence of first-pass effects may limitcharacterize the immediate postnatal period. Thesethe systemic bioavailability of the compound. Thisdevelopmental changes cause major age-related

may lead to lower plasma concentrations of thechanges in drug absorption, distribution and elimina-compound and reduced exposures.tion (metabolism and excretion), which may have a

significant impact on plasma concentrations and the2.1. Gastrointestinal absorptionresultant exposure outcomes. Additionally, matura-

tion is a dynamic process influenced by a plethora ofTable 1 summarizes the age-dependent anatomicalgenetic and environmental factors. The rate and

and physiological factors that may influence the ratepattern of maturation of each pharmacokinetic pro-and/ or extent of gastrointestinal absorption. De-cess may vary greatly among infants. This may resultvelopmental changes in one or any combination ofin marked interindividual variability in phar-these factors may explain the differences in absorp-macokinetics such that infants of similar age may


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Table 1a

Age-dependent factors affecting gastrointestinal absorption and the resultant pharmacokinetic outcome relative to adult levels

Newborn Neonate Infant

(full-term) (1 day1 month) (1 month2 years)

Physiological factorGastric pH 13 .5 |Adult

Gastric emptying time Reduced (variable) Reduced (variable) Increasedb b

Intestinal surface area Reduced Reduced |Adult

Intestinal transit time Reduced Reduced Increased

Pancreatic and biliary function Very immature Immature |Adult

Bacterial flora Very immature Immature Immature

Enzyme/transporter activity Very immature Immature Approaching adult

Pharmacokinetic outcome

Rate and extent of absorption Variable Variable $Adult

Gastrointestinal first-pass effects Very reduced Reduced Approaching adult

aAdapted from Besunder et al. [7].

b

From Ref. [8].

tive characteristics between newborns and young pH in the newborn and young infant may involve

infants relative to the adult. The developmental enhanced bioavailability of weakly basic compounds,

pattern of these processes may be highly variable and but reduced bioavailabilities of weakly acidic com-

environmental factors (i.e., diet, concomitant drugs) pounds. This may explain the increased bioavail-

[5], genetic factors and underlying pathophysiology ability of ampicillin and penicillin G (basic drugs)

(electrolyte abnormalities, endocrinopathies, CNS [1719] and decreased bioavailability of phenobarbi-

disorders, gastrointestinal disease) [6] may poten- tal (acidic drug) [19,20] observed in young infants.

tially influence their postnatal developmental pattern. Certain compounds require pancreatic exocrine

In general, newborns exhibit a slower rate of and biliary function for adequate absorption. New-

absorption [6]. Age-dependent differences in the borns have immature pancreatic and biliary functionextent of absorption (bioavailability) remain largely at birth [21]. The levels of most pancreatic enzymes

unknown [8]. However, bioavailability (the fraction are significantly reduced [22], and bile formation,

of parent compound reaching the systemic circula- bile acid pool size (50% adult values), bile acid

tion) will likely change with postnatal age due to synthesis and metabolism, and bile acid intestinal

maturation of the processes governing absorption. absorption are all reduced in the newborn [2325].

Pancreatic and biliary function rapidly develop in the

2.1.1. Gastrointestinal secretions postnatal period [22,26]. A deficiency of bile salts

Gastrointestinal pH affects the absorption of weak- and pancreatic enzymes may result in a reduction in

ly acidic and basic organic compounds. At birth, the bioavailability of those drugs that require

newborns have an alkaline gastric pH (pH 68) solubilization or intraluminal hydrolysis (i.e., pro-

[9,10]. Gastric acid production increases over the drug esters) for adequate absorption.next 2448 h to achieve adult pH levels (pH 13)

[1113]. Following this initial burst of hydrochloric 2.1.2. Gastrointestinal motility

acid secretion, gastric acid production declines and Gastrointestinal motility may affect the rate and/

gastric acidity remains relatively low in the first or extent of drug absorption. In general, newborns

months of life [11,14]. Postnatal increases in gastric exhibit delayed gastric emptying rates and prolonged

acid production generally correlate with postnatal intestinal transit times relative to the adult [27,28].

age [15] and, on a per kg basis, adult levels are The full-term newborn infant demonstrates quali-

approached by 2 years of age [16]. tatively similar gastrointestinal motility patterns with

The pharmacokinetic consequences of high gastric the adult, but premature infants exhibit disorganized


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and inefficient motility patterns [29,30]. In general, The developmental maturation of gastrointestinal

feeding triggers the postnatal development of gas- Phase II conjugation enzymes [4247] remains

trointestinal motility [5]. Reduced gastrointestinal unknown. However, b-glucuronidase activity of the

motility may have variable and unpredictable effects infant small intestine has been reported to exceed

on drug bioavailability in newborns and young adult activities by as much as 7-fold [48]. Thisinfants. In general terms, delayed gastric emptying enhanced b-glucuronidase activity may enable re-

may reduce the rate of drug absorption since the absorption of glucuronide drug conjugates. For drugs

small intestinal mucosa acts as the principal absorp- that undergo enterohepatic recirculation (i.e.,

tive site for most drugs. Alternatively, slower intesti- chloramphenicol, indomethacin) b-glucuronidase ac-

nal transit times may improve drug bioavailability tivity enhances their bioavailability.

due to longer retention times in the small intestine. The adult intestinal tract functionally expresses

The exact effect of developmental maturation of various members of the ATP-binding cassette and

gastrointestinal motility on drug bioavailability de- solute carrier transporter families [49,50]. These

pends upon the physico-chemical properties of the transporters may have an important impact on drug

drug and its interaction with the anatomical and absorption and bioavailability in the small intestine

physiological factors of the gastrointestinal tract. [51], but their exact role remains largely unknown.

The literature provides evidence of postnatal matura-

2.1.3. Gastrointestinal metabolism and transport tion of transport protein activities in other organ

Bacterial flora, principally concentrated in the systems [5258] suggesting gastrointestinal transpor-

ileum and colon [31], may influence the extent of ter function may also undergo a postnatal maturation.

drug absorption due to its influence on gastrointesti-

nal motility and ability to metabolize compounds 2.2. Gastrointestinal first-pass effects

[32]. At birth, infant gastrointestinal flora is very

immature and little information is available on the The gastrointestinal tract may play an important

effect of postnatal maturation of bacterial flora on role in the first pass metabolism of an orally adminis-

bioavailability [32,33]. In general, the bacterial flora tered compound [51]. Consequently, developmental

of the infant gastrointestinal tract approaches adult maturation of gastrointestinal metabolic and transport

populations by 4 years of age [34]. function may have significant consequences in gas-The proximal small intestine acts as the principal trointestinal first-pass effects and oral bioavailability.

absorptive site and site for significant first-pass In adults, some drugs undergo extensive metabolism

effects for many orally administered compounds. In in the gastrointestinal tract with a concomitant

the adult, the small intestinal mucosa functionally marked reduction in their oral bioavailability [59

expresses a limited number of phase I and phase II 61]. Immature gastrointestinal metabolic reactions

enzymes and their expression has led to significant may result in improved oral bioavailability as gas-

inter- and intra-individual variability in oral bioavail- trointestinal first-pass metabolism has less influence

ability [35]. Cytochrome P450 (CYP) 3A4 is the on the extent of absorption of such drugs. Converse-

predominant CYP enzyme expressed in enterocytes ly, some drugs are dependent upon carrier-mediated

[36,37], and CYP2C has the second highest expres- uptake systems in the intestinal mucosa for their

sion levels [37].Very low activity levels for CYP1A1 efficient absorption [62]. Immature development of[38] and CYP2D6 [35,39] were detected in intestinal transport function may lead to significantly reduced

microsomes. The maturation of CYP enzymes in the oral bioavailability.

intestinal mucosa remains largely uninvestigated. Some transporter proteins expressed in the intesti-

One study reported significantly lower CYP3A4 nal mucosa promote the active extrusion of drug

activity levels in intestinal microsomes from infants from the enterocyte back into the lumen of the

aged 03 months and a developmental increase in gastrointestinal tract after its absorption (i.e., MDR1)

activity with age [40]. As well, CYP3A7, the fetal [63,64]. These transporter proteins compete with

hepatic form of CYP3A, appears to lack expression absorption processes and may decrease the rate of

in extrahepatic tissues [41]. absorption and, potentially, the oral bioavailability.


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The interplay between CYP3A4 and the active efflux postnatal period [65], while total body fat increases

transporter, MDR1, illustrates this concept [63,64]. progressively in the first months of life [66].

Again, immature development of these active efflux Age-related changes in total body water are pri-

processes may result in enhanced oral bioavailability. marily attributed to decreases in the relative per-

The exact effect of postnatal maturation on oral centage of extracellular water [65,67]. Extensivebioavailability will depend upon the interaction of tissue binding or partitioning into fat contribute to

the principal factors influencing bioavailability large V values. Polar compounds generally exhibit Vd d

(physico-chemical properties of the compound, equivalent to total body water or blood volumes.

physiology and anatomy of the gastrointestinal tract, Hence, age-related changes in fat, muscle and total

metabolic enzymes, transport processes) [51] and the body water composition may produce significant

degree of their postnatal maturation. quantitative changes in V and plasma concentrations.d

In newborns, the high relative proportion of total

body water and low proportion of fat results in a

general increase in V for water-soluble compoundsd3. Distribution

and a lower V for fat-soluble drugs relative to adults.d

Key pharmacokinetic parameters (i.e., clearancePostnatal changes in body composition, extent of and volume of distribution) are often normalized

binding to plasma proteins and tissue components,according to total body weight or body surface area.

and hemodynamic factors (cardiac output, tissueTherefore, it is critical to understand the develop-

perfusion and membrane permeability) may altermental changes in these body indices with postnatal

distribution characteristics in the developing infant.age, which is depicted in Fig. 1. While both total

The apparent volume of distribution (V ) provides ad body weight and surface area rise steadily during the

useful marker to assess age-related changes in drugfirst year of life, a considerable change in their ratio

distribution.occurs during the initial 3 months of life.

Developmental changes in V may also relate tod

3.1. Body composition and tissue perfusion postnatal enhancements in cardiac output, organ

blood flows and tissue perfusion, changes in mem-

Body composition may significantly affect drug brane permeabilities [7072] and maturation ofV . Changes in body composition correlate with both carrier-mediated transport systems [5558,7375],

d

gestational and postnatal age. Table 2 illustrates total and changes in tissue binding affinities or capacities

body water, total protein and total fat content in the since newborns and young infants have significantly

newborn, during infancy and in the adult stages.

Total body water decreases significantly in the early

Table 2

Developmental changes in body composition (reported as aa

percentage of total body mass)

Age Body Water Protein Fat

mass

(kg)

Newborn: full-term 3.5 74 11 14

4 months 7.0 61.5 11.5 27

12 months 10.5 60.5 15 24.5Fig. 1. Age-related changes in body weight, body surface areab

Adult 70 5560 (BSA) and the ratio of body weight to BSA. Data from the Center

aAdapted from Geigy Scientific Tables [66]. for National Health Statistics at the CDC [68] and Taketomo et al.

bObesity decreases the percentage of total body water. [69].


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greater liver, kidney and brain masses relative to

total body mass [66,67,76].

3.2. Plasma protein binding

Postnatal development of plasma protein binding

may affect both the distribution and elimination of

compounds in the newborn and young infant. In

general, newborns and young infants exhibit larger

unbound fractions of a compound relative to the

adult. This may result in enhanced distribution intoFig. 2. General pattern of ontogeny for albumin (ALB) and alpha

tissues and a larger V . Age-related differences ind 1-acid glycoprotein (AAG) in newborns and infants. Data adapted

plasma protein binding affinity, plasma protein con- from [86] and are expressed as fraction of adult serum con-centration (mg/dl).centrations and availability of competing endogenous

compounds largely explain the differences in the

extent of binding.

Compounds bind principally to albumin and a -acid glycoprotein plasma concentrations and the1

alpha -acid glycoprotein. Albumin is the major fraction bound in the infant relative to the adult [86].1

plasma protein [77], and concentrations of alpha - Several endogenous substances (i.e., bilirubin,1acid glycoprotein, an acute phase reactant protein fatty acids) may compete for plasma protein binding

[78], fluctuate significantly in response to various sites [82,8789]. This competition may further re-

diseases, trauma or chemical insult [79,80]. In gener- duce the bound fraction of a compound in the

al, the newborn may exhibit lower binding affinities newborn, or cause displacement of the endogenous

of compounds (i.e., penicillin, phenobarbital, pheny- molecule from its protein binding sites. For instance

toin and theophylline) [81] to albumin and a -acid hyperbilirubinemia reduces the binding of the acidic1

glycoprotein [8284]. High unbound fractions may drugs ampicillin, penicillin, phenobarbital and

lead to significantly larger V values, and enhanced phenytoin [81,90]. Conversely, displacement of bil-d

renal clearance by glomerular filtration and hepatic irubin by drugs (i.e., sulfonamides) may enhance theclearance of low extraction ratio compounds in the risk for bilirubin encephalopathy [7]. Hepatic and

newborn. renal disease, hypoproteinemia due to malnutrition,

Developmental changes in plasma protein con- cystic fibrosis, burns, malignant neoplasms, surgery,

centrations have the most significant affect on the trauma and acidosis may further decrease plasma

extent of plasma protein binding in the young infant. protein drug binding due to decreased protein syn-

Total plasma protein levels are lower in the newborn thesis or competition for binding.

relative to the adult [85]. Lower plasma protein

levels reduce the plasma protein binding capacity in

the newborn. Fig. 2 illustrates the postnatal increase

in albumin and alpha -acid glycoprotein concen- 4. Elimination1

trations relative to adult levels. A strong correlationexists between the postnatal increase in plasma Systemic clearance provides a measure of the

albumin concentrations and the fraction bound [86]. efficiency of elimination and is often the most

This suggests adult binding characteristics (i.e., important pharmacokinetic determinant of plasma

unbound fraction) for a given compound and the concentrations and resultant response (see Eq. (1)).

ratio of infant and adult albumin concentrations may In general, hepatic and/or renal elimination path-

provide an estimate of infant unbound fractions for ways effect the removal of most compounds from the

that compound [86]. On the other hand, a weak body. These pathways are generally underdeveloped

correlation exists between the postnatal increase in and inefficient in the newborn. The various pathways


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of elimination mature at different rates and patterns thione conjugation, and acetylation. Since most

of development and maturation to adult levels (ad- compounds are eliminated by more than one meta-

justed for body weight differences) is generally bolic pathway, postnatal changes in the efficiency of

achieved after the first year of postnatal life. Recent Phase I and Phase II reactions, differences in their

in vitro and in vivo probe substrate data have rate and pattern of development, and changes in theprovided important information on the maturation hepatocellular distribution and expression of Phase I

characteristics of hepatic and renal elimination mech- and Phase II enzymes [104] may have a significant

anisms (reviewed in Alcorn and McNamara, 2002) impact on the qualitative and quantitative charac-

[91]. This data provides the basis for the proceeding teristics of hepatic elimination in the newborn and

discussion. Additionally, for more in depth discus- developing infant. To predict the exact nature of

sion of the maturation of systemic clearance mecha- these consequences requires an understanding of the

nisms the reader is referred to excellent reviews by postnatal maturation of the individual hepatic meta-

Hakkola et al. [92], Ring et al. [93], Gow et al. [94], bolic pathways that mediate drug and toxicant re-

McCarver and Hines [95], Hines and McCarver [96], moval from the body.

de Wildt et al. [97], and Hayton [98].4.1.1.1. Cytochrome P450 enzyme-mediated metabo-

4.1. Hepatic clearance lism

The CYP enzymes represent a superfamily of

Hepatic blood flow, plasma protein binding and heme-containing enzymes [105]. CYP1A2, CYP2A6,

intrinsic clearance (defined as the maximal en- CYP2B6, CYP2Cs, CYP2D6, CYP2E1, and

zymatic or transport capacity of the liver) constitute CYP3A4/7 comprise the principal CYP enzymes

the physiological determinants of hepatic clearance important in drug and toxicant metabolism [106

[99,100]. Each of these determinants undergoes 108]. The rate and pattern of postnatal CYP enzyme

significant postnatal changes, and their maturation development may have a significant impact on

results in an enhanced capacity for hepatic elimina- therapeutic efficacy and toxicant susceptibility in the

tion of compounds with advancing postnatal age. newborn and developing infant. Interindividual dif-

ferences in their developmental patterns, genetic

4.1.1. Intrinsic clearance polymorphisms, and their induction/ inhibition po-Intrinsic clearance processes principally govern tential further complicate the role of CYP enzyme

the capacity of newborns to eliminate drug by the maturation on pharmacokinetics in the newborn and

liver. Although hepatocellular transport and biliary young infant.

excretion processes contribute to intrinsic clearance The postnatal maturation of CYP enzymes is

and are deficient at birth [74,101,102], hepatic evidenced in numerous literature reports of short-

biotransformation processes have the greatest impact ening half-lives and enhanced hepatic elimination of

on hepatic drug elimination in the developing infant. drugs in developing infants [109,110]. These studies

Phase I and Phase II reactions principally mediate suggest hepatic metabolic pathways undergo rapid

the metabolism of compounds in the developing postnatal development. Recently, in vitro studies

infant. Often a compound undergoes sequential have examined the maturation of individual CYP

metabolism with Phase I metabolic reactions preced- enzymes in age-dependent fetal and infant hepaticing Phase II metabolism [103]. microsomes [111115]. These studies corroborate

Of the phase I reactions, cytochrome P450 (CYP) the findings of the in vivo studies and have further

enzymes have the most important role in the elimina- elucidated the maturation characteristics of individ-

tion of most compounds. The postnatal maturation of ual CYP enzymes. As well, these studies have shown

other Phase I enzymes, such as the alcohol and the CYP enzymes mature at characteristic rates and

aldehyde dehydrogenases, esterases and the flavin- patterns of development and may be grouped accord-

containing monooxygenases, are reviewed in Hines ing to their general developmental pattern of activity

and McCarver, 2002 [96]. Important phase II re- [116]. Fig. 3 highlights the general pattern of CYP

actions include glucuronidation, sulfation, gluta- enzyme development as a fraction of adult levels


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biotransformation and, in general, CYP enzyme-me-

diated metabolism improves with postnatal age and

generally approaches adult levels only after the first

year of life [117,120]. Table 3 summarizes the

maturation of individual CYP enzyme activity levelsbased upon in vitro determinations of CYP enzyme

activity in fetal, infant and adult age group hepatic

microsomes [111115].

4.1.1.1.1. Maturation of individual CYP

enzymes Fetal hepatic microsomes exhibit negligible

CYP1A2 enzyme activity [107,121,122]. CYP1A2

enzyme activity remains very low after birth and

significant in vitro activity is detected only by 13

months of age [112]. By the first year of lifeFig. 3. General pattern of postnatal development of the hepatic

CYP1A2 enzyme activity levels are only 50% adultclearance pathways in newborns and infants. Data adapted from

values and mature to adult activity levels sometime[91] and are expressed as fraction of adult clearance values after a year of age [112,120]. This pattern of(ml/min/kg). The general classification was adapted from Cres-teil, 1998 [116]. (CYP, cytochrome P450 enzyme; UGT, Uridine development explains the long half-life and low59-diphosphate-glucronosyltransferase; ST, Sulfotransferase; NAT, systemic clearance values of theophylline in the

N-acetyltransferase; GST, Glutathione-S-transferase).newborn [123]. Immature CYP1A2 enzyme develop-

ment prevents the biotransformation of theophylline

based upon enzyme activity values (normalized to resulting in prolonged half-lives in the newborn and

mg microsomal protein) from age-specific fetal, infant. Significant increases in theophylline systemic

neonatal and infant hepatic microsomes [116]. clearance values are observed only after 13 months

In vitro assessments have revealed significantly of age [123,124]. This pattern of theophylline clear-

lower levels of CYP enzyme protein and activity in ance with advancing postnatal age reflects the post-

the fetus (total CYP enzyme protein levels are one- natal development of in vitro CYP1A2 enzyme

third adult levels) [107,117,118]. These data are activity in the infant.consistent with literature reports demonstrating the Fetal livers fail to express CYP2A6 and CYP2B6

ability of the fetal liver to metabolize a variety of enzyme activity [107,122]. Otherwise, the postnatal

drug substrates [116,119]. For most CYP enzymes, development of CYP2A6 and CYP2B6 remains

though, fetal activity levels are only a small fraction largely unknown. Both CYP enzymes likely achieve

of adult activity levels, and parturition triggers their adult capacities only after the first year of life [120].

postnatal development [9294,116]. Consequently, Fetal and newborn (,1 week of age) livers

the newborn has a limited capacity for hepatic demonstrate very limited CYP2C enzyme activity

Table 3

In vitro cytochrome P450 (CYP) enzyme activity in age-specific fetal and infant hepatic microsomes as a fraction of adult activity (nmol21 21

min mg microsomal protein )CYP Fraction of adult activity

enzymeFetus ,24 h 17 d 828 d 13 m 312 m 115 y

1A2 0.05 0.12 0.10 0.20 0.39 0.46 1.10

2C 0.02 0.03 0.42 0.29

2D6 0.04 0.04 0.09 0.24

2E1 0.21 0.31 0.36 0.46 0.39 0.80

3A4 0.03 0.08 0.13 0.29 0.34 0.43 1.08

3A7 5 9.5 13 6 3 2

Adapted from Refs. [111115].


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[118,125]. Within the first month of postnatal life, activity and express limited CYP3A4 enzyme activi-

CYP2C enzyme activity surges to 50% adult levels ty (|10% adult levels) [111,122]. CYP3A7 enzyme

[114,117]. After this surge of activity, CYP2C activity levels peak 1 week after parturition, then

enzyme activity levels decline slightly for the first declines significantly during the first year of life

year of life and adult levels are reached sometime [111,120]. Adult livers may express only 10% fetalafter 1 year of age [114,117,120]. As a substrate of levels [111,132]. During the postnatal period, activi-

the CYP2C enzyme subfamily, diazepam metabolite ty levels of CYP3A4 enzyme increase concomitantly

urinary levels are consistent with the in vitro pattern with the decreases in CYP3A7 enzyme activity

of CYP2C enzyme development. Newborns exhibit [111]. CYP3A4 enzyme activity reaches 3040%

very low urinary diazepam metabolite levels [114]. adult levels by 1 month of age and adult levels by 1

However, diazepam urinary metabolite levels in- year [111,120]. The pharmacokinetic consequences

crease significantly in infants greater than 1-week- of this postnatal developmental switch from

old [114]. Thereafter, metabolite levels remain rela- CYP3A7 to CYP3A4 remain largely unknown since

tively stable in children up to 5 years of age [114]. the substrate profile of CYP3A7 enzyme has re-

Fetal livers may express very low levels of ceived limited investigation. However, some studies

CYP2D6 enzyme activity [107,113]. A dramatic suggest newborns and adults will exhibit significant

increase in CYP2D6 activity occurs in the immediate differences in their capacity to eliminate known

postpartum period. By the first month of life, CYP3A4 enzyme substrates. For example, premature

CYP2D6 enzyme activity levels reach |30% adult and full-term newborns eliminate the CYP3A4 en-

levels [113], and CYP2D6 maturation may be com- zyme substrate, midazolam, with poor efficiency

pleted by 1 year of age [120]. In vivo assessment of [133]. A 5-fold increase in the elimination efficiency

the hepatic clearance of CYP2D6 substrates is of midazolam occurs by 3 months of age [134].

lacking in the newborn and young infant. These data suggest midazolam is not an efficient

Fetal hepatic microsomes may express low levels CYP3A7 enzyme substrate.

of CYP2E1 enzyme activity [126]. Parturition trig-

gers a dramatic increase in CYP2E1 enzyme activity 4.1.1.2. Phase II metabolism

within the first 24 h of life [115]. CYP2E1 enzyme Phase II or conjugation reactions contribute sig-

activity levels achieve 50% adult levels by 13 nificantly to the elimination of a wide variety ofmonths of age and development is essentially com- exogenous and endogenous compounds. Glucu-

plete after 1 year of age [115]. ronidation, sulfation, acetylation, glutathione conju-

CYP3A subfamily is the most abundantly ex- gation, comprise the most important Phase II path-

pressed CYP enzyme in the liver [106,127]. ways in drug and toxicant metabolism. In general,

CYP3A4 enzyme is the principal enzyme of the adult changes in the expression patterns of the different

liver [106], while fetal livers predominantly express Phase II enzymes or changes in their catalytic

CYP3A7 enzyme [111,128,129]. Although CYP3A4 efficiency may occur with development. Such

and CYP3A7 enzymes exhibit 95% similarity in their changes may have important consequences on the

nucleotide sequences [130], important differences in elimination of compounds in the newborn and young

substrate specificities exist between these two infant. In general, inefficient conjugation capacity of

CYP3A enzymes [107,111,131]. Few studies have the newborn will result in a significant reduction inexamined the substrate profile of CYP3A7 enzyme. the ability of the newborn to eliminate both exogen-

The ability of fetal livers to metabolize a wide ous and endogenous compounds. Table 4 and Fig. 3

variety of substrates [119] suggests CYP3A7 enzyme summarize the known maturation patterns of im-

also may metabolize a wide range of substrates and portant Phase II enzymes. For a more in depth

demonstrate some substrate overlap with CYP3A4 discussion of the development of Phase II metabolic

enzyme. pathways, the reader is referred to the review by

Total CYP3A enzyme protein levels remain rela- McCarver and Hines [95].

tively constant throughout development [111]. Fetal 4.1.1.2.1. Maturation of individual conjugation

livers demonstrate high levels of CYP3A7 enzyme reactions The uridine 59-diphosphate-glucrono-


11/20


Table 4 capacity to eliminate morphine, and adult levels wereMaturation patterns of phase II enzymes achieved by 630 months of age [146,147].Phase II enzyme Maturation pattern Sulfotransferases (ST) consist of a number of

individual enzymes and have substrate specificitiesUGT Fetal livers exhibit limited enzyme activity;

activity |25% adult levels at 3 months; that demonstrate significant overlap with the UGTmaturation is isoforms specific; adult enzymes [148]. Although changes in activity of theactivity levels achieved by 630 months. individual ST enzymes with development occur, the

data on their development is limited and confusing.ST Fetal livers exhibit significant activity;

In general, fetal, newborn and infant livers expressmaturation is isoform specific.significant ST activity, and sulfate conjugation is a

GST Fetal livers exhibit significant activity; relatively efficient pathway at birth [149151]. Con-maturation is isoform specific; total sequently, the newborn and young infant may elimi-activity remains stable throughout infancy.

nate ST enzyme substrates very efficiently. For

instance, the ST and UGT enzyme substrate ritod-NAT Fetal livers exhibit low activity; lowactivity at birth through the first months of rine, a b -adrenoceptor agonist, underwent extensive

2

life; adult levels achieved after 1 year of age. sulfate conjugation in infants [149]. The study

demonstrated no age-related differences in the over-UGT, Uridine 59-diphosphate-glucronosyltransferase; ST,Sulfotransferase; NAT, N-acetyltransferase; GST, Glutathione-S- all systemic clearance of ritodrine, only quantitativetransferase. differences in metabolite levels (glucuronide conju-

gates and sulphate conjugates) between infants and

adults [149].

syltransferases (UGT) enzymes consist of two Glutathione-S-transferases (GST) represent a

families, UGT1 and UGT2, containing more than 18 superfamily of dimeric enzymes responsible for the

different enzymes [97,135]. More than one UGT detoxification of a number of potentially toxic drug

enzyme may participate in the metabolism of a single or drug metabolites [152]. Five different subunit

substrate [136,137], and the maturation of UGT classes (m, a, u, p and z) of GST enzymes have

enzyme capacity is isoform specific [97,138]. Conse- been classified [152,153]. As with the ST enzymes,

quently, the developmental rate and pattern of in- the GST enzymes demonstrate age-related expressiondividual UGT enzymes may explain the tremendous of individual enzymes in the liver [154156]. For

variability reported in the glucuronidation capacity of example, preterm newborn livers exhibited 60%

newborns and infants. In their review on the de- greater activity towards chloramphenicol than fetal

velopmental maturation of glucuronidation capacity livers, but showed similar activity levels towards

in the infant, de Wildt et al. suggest the clinical chlorodinitrobenzene [157]. However, the literature

relevance of the development of individual UGT remains sparse and presents conflicting information

enzyme capacity in infants remains unclear [97]. with respect to individual enzyme development

As a whole, newborns and young infants demon- [156,157]. In general, though, GST activity is rela-

strate inefficient glucuronidation capacity relative to tively well-developed in the newborn and infant, and

the adult [139141]. Fetal livers exhibit limited UGT total GST activity may remain relatively stable

enzyme activity [142,143]. Fetal hepatic microsomes throughout development [158]. The clinical signifi-(1527 weeks gestation) catalyzed morphine glucu- cance of the quantitative and qualitative differences

ronidation at only 1020% the efficiency of adult in the developmental expression of individual GST

hepatic microsomes [144,145]. Parturition triggers an enzymes remains unknown, but may have important

increase in UGT enzyme activity and UGT enzyme implications in toxicant susceptibility.

activity achieves |25% adult levels by 3 months of N-acetyltransferases (NAT) consist of two en-

age [143]. The in vivo postnatal elimination pattern zymes, NAT1 and NAT2, and NAT2 demonstrates

of the UGT enzyme substrate, morphine, is con- polymorphic activity [159161]. Very limited data

sistent with the in vitro studies. Premature and full- exists on the developmental expression of NAT1 and

term infants have a markedly reduced and variable NAT2 enzyme activity. Fetal livers express activity


12/20


towards several NAT enzyme substrates, but at much assessment of elimination capacity in the newborn

lower levels than the adult [47,162]. Consequently, and young infant.

the newborn exhibits a limited capacity to acetylate

substrates. The acetylation status of the infant may 4.1.2. Hepatic first-pass effects

reflect adult levels only well past the first year of life For many drugs subject to first-pass effects,[163165]. hepatic metabolism results in a significant reduction

in the oral bioavailability of a compound. Postnatal4.1.1.3. Consequences of variability in the postnatal maturation of metabolic enzyme pathways and hepa-

maturation of phase I and phase II reactions tocellular transport systems may result in significant

Many compounds undergo multiple routes of differences in the oral bioavailability of compounds

metabolism. Quantitative and qualitative differences in the newborn and young infant relative to the adult.

in the developmental expression profiles of metabolic For all orally administered compounds, plasma pro-

pathways of the liver may modify the rate and tein binding and intrinsic clearance determine the

pattern with which newborns and infants eliminate extent of parent drug bioavailability [99]. Newborns

compounds throughout development. These inter- generally exhibit lower plasma protein binding ca-

individual differences may lead to altered metabolite pacities. Higher unbound fractions of an absorbed

profiles as the relative contribution of the different compound may theoretically enhance oral clearance

routes of metabolism may vary with infant age. and result in lower oral bioavailability of the com-

Differences in metabolite profiles become significant pound. For most drugs, intrinsic clearance has the

when a particular metabolite has pharmacological or most important effect on bioavailability. At birth,

toxicological activity. Consequently, the rate, pattern immature Phase I and Phase II metabolic enzyme

and extent of metabolic pathway maturation are pathways and hepatocellular transport processes may

important considerations in the pharmacokinetic significantly reduce the extent of first-pass hepatic

consequences of postnatal maturation of hepatic metabolism of an absorbed compound. Inefficient

clearance pathways. Interindividual differences in the hepatic metabolism in the newborn may cause

rates and patterns of individual elimination pathway enhanced oral bioavailabilities relative to the adult.

maturation may largely explain the tremendous Maturation of the hepatic metabolic pathways will

interindividual variation observed in the capacity of result in age-related reductions in oral bioavail-newborns and infants to eliminate drugs. Superim- ability. As with hepatic clearance, interindividual

posed upon the interindividual variability in metabol- differences in the rate and pattern of metabolic

ic enzyme maturation is the influence of metabolic enzyme pathway maturation may cause significant

enzyme induction and/ or inhibition. In utero and/ or interindividual variation in oral bioavailability during

postnatal exposure to certain exogenous or endogen- postnatal development. Hence, postnatal maturation

ous compounds may cause rapid enzyme induction of hepatic metabolism may greatly influence thera-

or inhibition in the fetus, newborn and infant [166]. peutic efficacy and toxicant susceptibility because

This will further exacerbate the variable rate and hepatic metabolism may determine the both the oral

pattern of enzyme maturation. For example, new- bioavailability of a compound and the efficiency with

borns treated concomitantly with barbiturates, a which the newborn or young infant may remove that

CYP2C inducer [114], exhibited a marked reduction compound from the body.in diazepam (a CYP2C substrate) half-lives (t 5

1 / 2

1861 h) as compared with newborns treated with 4.2. Renal clearance

diazepam alone (t 53162 h) [114,167]. Further-1 / 2

more genetic polymorphisms in CYP2D6, CYP2C9, Renal clearance mechanisms include glomerular

CYP2C19, CYP2E1, UGT and NAT [168] may filtration (GFR), tubular secretion and tubular re-

further enhance the interindividual variability in drug absorption. At birth, these renal clearance mecha-

elimination characteristics observed in infants. Poly- nisms are incompletely developed and renal elimina-

morphisms in drug metabolism and the potential for tion capacity of the newborn is significantly compro-

enzyme induction and/or inhibition complicate any mised [169171]. During late gestation and early


13/20


postnatal development profound anatomical and average and a slower pattern of GFR development

functional changes in the kidney greatly enhance during the first 12 weeks postpartum as compared

renal elimination efficiency in the first few months of with the full-term infant [4,183,196]. With comple-

life [172,173]. Renal functions demonstrate a rapid tion of nephrogenesis and maturation of glomerular

maturation and generally reach adult levels before 1 function, enhancements in GFR in the preterm infantyear of age [174176]. Maturation of glomerular will proceed at the same rate as full-term infants

filtration and renal tubular functions proceed at [183]. However, even by 5 weeks of age the absolute

different rates and patterns resulting in marked value for GFR remains lower in preterm infants

interindividual variability in renal elimination ef- [183]. This functional delay in GFR in preterm

ficiency. infants is an important consideration in the estima-

The anatomical and functional development of the tion of an infants capacity for renal elimination.

kidney continues throughout gestation into the early Interestingly, Fig. 4 illustrates infant GFR, on an

postnatal period. Nephrons increase in number until ml/ min/ kg basis, is roughly comparable to the adult

nephrogenesis is completed at 36 weeks of gestation [185]. This implies adult renal clearance values

[172,173,177,178]. Prior to 36 weeks gestation, then, normalized to a body weight may reasonably predict

changes in renal function principally correlate with infant renal clearances on a body weight basis.

increases in the number of nephrons [179181].

Incomplete nephrogenesis in the pre-term newborn 4.2.2. Renal tubular function

will compromise glomerular and tubular function At birth, the renal tubules exhibit significant

[182]. Functional maturation and growth processes anatomic and functional immaturity [197]. Incom-

explain the changes in renal elimination capacity in plete anatomical development of renal tubules com-

the full-term infant [98,172]. In general, postnatal promises both passive reabsorption [188,198] and

functional maturation of the kidney is associated active secretion and reabsorption processes [199

with enhancements in renal blood flow, improve- 201]. In addition to limited tubular size and func-

ments in glomerular filtration efficiency and the tional maturity, poor peritubular blood flow, reduced

growth and maturation of renal tubules and tubular urine concentrating ability, and lower urinary pH

processes [98]. values further compromise renal tubule function in

the newborn [202]. In general, renal tubular growth4.2.1. Glomerular filtration processes, maturation of renal tubular transport sys-

During the fetal stages, GFR capacity is signifi- tems, and redistribution of blood flow to the secret-

cantly reduced [172]. Parturition triggers enhance- ory areas of the kidney account for the enhancements

ments in both cardiac output and renal blood flow

and a dramatic decrease in renal vascular resistance

and a redistribution of blood flow within the kidney

[172,183185]. These hemodynamic changes cause a

rapid increase in GFR during the early postnatal

period [4,171,186190]. At birth, GFR, normalized

to body surface area, in the full-term infant is 10152

ml/ min/ m [169,171], but increases to 2030 ml /2min/ m within the first 2 weeks of life [171,191]. By

6 months of age, infant GFR, normalized to body

surface area has approached adult levels (73 ml/2

min/m ) [192]. Rapid improvements in GFR result

in rapid enhancements in the renal clearance ofFig. 4. General pattern of postnatal development of the renalcompounds principally eliminated by GFR.clearance pathways in newborns and infants. Developmental

Postnatal improvements in GFR correlate withchanges in glomerular filtration rate (GFR), renal tubular secretion

gestational age rather than postnatal age [4,193 (TS) and renal blood flow (Q ). Data adapted from [98] and areR

195]. Premature infants exhibit lower GFR values on expressed as fraction of adult clearance values (ml/min/kg).


14/20


in renal tubular function during postnatal develop- tional immaturity of absorption, distribution, metabo-

ment [171,187,203]. As the infant develops, matura- lism and/or excretion processes contribute to the

tion of renal tubular function generally exhibits a disparate responses observed between newborns,

more protracted time course than GFR. This infants and adults. Premature infants present a fur-

produces a functional glomerulotubular imbalance ther complication as the anatomical and functionaluntil renal tubule maturation is completed by 1 year immaturity of the organs and other biochemical and

of age [204,205]. physiological processes involved in drug phar-

Numerous protein carrier systems mediate active macokinetics is further exacerbated. An assessment

renal excretion and reabsorption. Their postnatal of the therapeutic efficacy or toxicant susceptibility

development at the renal tubular epithelium and their of a newborn to an exposure will require a careful

impact on renal elimination efficiency in the new- consideration of the developmental aspects of phar-

born and infant remains largely unknown. Func- macokinetic processes. In general, the combined

tionally, the kidney exhibits a reduced capacity to effects of age-related changes in each phar-

excrete weak organic acids like penicillins, sulfon- macokinetic process on plasma levels of a compound

amides, and cephalosporins [200,201]. Newborn are poorly understood. Clinical studies encompassing

kidneys excrete p-aminohippurate (PAH), a substrate newborns and infants within narrow postnatal age

for the organic anion transporters, at 2030% adult groups are needed to enhance our understanding of

levels [187], and adult excretion levels are ap- the pharmacokinetic and clinical consequences of

proached by 78 months of age [176]. Premature postnatal maturation of absorption, distribution, me-

and full-term infants excrete furosemide, a PAH tabolism and excretion processes. Such information

transport pathway substrate, slowly with plasma half- will help to establish more effective guidelines to

lives of 19.9 and 7.7 h, respectively, as compared predict an exposure outcome in a newborn or young

with 0.5 h in the adult [206,207]. In utero or infant infant and to ensure safe exposures to therapeutic or

exposure to certain agents may induce or inhibit inadvertent compounds.

renal tubular transport functions [174]. Transport

induction or inhibition may compound the variability

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