2a-c imp walsh drug transport, absorption 2011

8/4/2019 2a-c IMP Walsh Drug Transport, Absorption 2011

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Drug Names

Chemical name

Code name

Chosen by manufacturer during drug development

Proprietary name Chosen by manufacturer for marketing purposes

Also referred to as brand or trade name

Official name

Assigned by US Adopted Name Council

Also referred to as generic or nonproprietary name Generic name

Official, nonproprietary name

Class name


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Procaine

4-aminobenzoic acid 2(diethylamino) ethyl

ester Local anesthetic

NOVOCAINE


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Physicochemical Properties of

Drug Molecules

ZnO N2O

C2H5OH


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Molecular weight

Stability in vitro and in vivo

Gas, liquid, or solid

Solubility in water and in oil

3-dimensional structure Ionizable groups


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Lipophilicity

Solubility in lipid relative to water

Measured by oil/water partition

coefficient

Drug concentration in oil versus water

Oil

Water


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Aspirin


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Amphetamine


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Influence of pKa

AH A- + H+

BH+ B + H+


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pKa

Aspirin

Weak acid

pKa of 3.5

Amphetamine

Weak base

pKa of 10


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Lidocaine pKa 8


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Henderson-Hasselbach

Relationship: pKa and pH

pH

% Unionizedacid base


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Acetylcholine

quaternary ammonium withfixed positive charge

+


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Stereoisomers

D vs L amphetamine

NEXIUM (single stereoisomer) vsPRILOSEC (racemic mixture)


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TPA

tissue plasminogen activator

Protein with 527 aa and MW of 70,000


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Pharmacodynamics

Mechanism of action

Clincal efficacy Clinical indication

Side effects and toxicity

Selectivity


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Pharmacokinetics

The time-course of:absorption

distribution

elimination

Factors that modifypharmacokinetic phenomenon


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Dose

Cp

absorption

distribution

elimination

EFFECT


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Objective of PK Analysis

Characterize absorption, distributionelimination kinetics Dose dependence

Species dependence

Identification of other variables

Predict concentration at site of action

Predict time course of drug effect Design dosage regimen and individualize

based on patient phenotype and genotype


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Biotransport

Passive diffusion through cellmembrane

Filtration

Carrier-mediated transport

Receptor-mediated endocytosis


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Passive Diffusion

First-order kinetic process Rate dependent on concentration gradient

Cellular structure Tight junctions

Lack of porosity

Chemical attributes

Lipophilicity Ionizable residues and pKa

Molecular weight


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Capillary PermeabilityPorosities Blood-Brain Barrier


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Lipophilicity


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Impact of Ionizable Groups

Ionization markedly decreaseslipophilicity

Drugs with fixed negative or positivecharge not readily transported bypassive diffusion Example of quaternary ammonium

compounds R2

R 1 N+

R4 R3


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Filtration

Transport in bulk flow of aqueous fluid

Rate dependent on

hydrostatic pressure molecular weight, size, charge, and binding to

excluded macromolecules

tissue porosity glomerular capillaries in kidney

choroid plexus in brain

sinusoids in liver


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Review of Medical Physiology, 2001


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Review ofMedical

Physiology,2001


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Fenestrated Capillary of Renal GlomerulusD. Vaughan, Oxford University Press, 2002


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Carrier-mediated Transport

Saturable kinetics

Substrate competition

Tissue differences inexpression of carriers


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Drug Transporters

Multidrug resistancep-glycoproteins

mdr gene products 170kD

Amphipathic cationicand neutral substrates

Verapamil sensitive

Multidrug resistance-associated proteins

MRP1-6, oatp 190kD

Organic anionicsubstrates

Probenecid sensitive


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MDR p-Glycoprotein

Efflux pump, cause of resistance to someantitumor drugs


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Drug Transporter Localization Intestinal mucosa

Hepatocyte

Proximal renal tubule

Brain

Vascular endothelium

Choroid plexus


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Receptor-mediated

Endocytosis

Importance in selective tissue uptake

Rate dependent on receptor expressionand membrane insertion

Saturable kinetics


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Dose

Cp

absorption

distribution

elimination

EFFECT


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Absorption Kinetics

Time-course of transport from site ofadministration to systemic circulation

Characterization by absorption half-life

percent dose absorbed (bioavailability)


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Routes of Administration


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Intravenous

100% bioavailability

Rate dependent on technique ofadministration, not physiological process

Importance of sterility, lack of particulates,

aqueous solubility of agent


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Subcutaneous

Uptake of high molecular weight

compounds into lymphatics Blood flow as rate-limiting factor for some

drugs

Improved bioavailability over oral route forsome drugs

Delivery devices for sustained release


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Inhalation

Rapid absorption of gases and vapors due to

high pulmonary blood flow low diffusional distance from alveolus to

blood

Route for localized delivery of drugs with

actions in pulmonary tissue


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Topical

Absorption through skin generally slow due tosurface layers of dead, keratinized cells

(stratum corneum)

Drugs with sufficient lipophilicity and potencymay have systemic clinical efficacy upon

topical application in transdermal patch Avoids first-pass effect


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Enteral Administration


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OralBioavailability may be low due to:

Mucosa as barrier

High MW

low lipophilicity

carrier-mediated extrusion


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Oral

Bioavailability may be low due to:

First-pass effectLumenal, mucosal and/or hepaticbiotransformation during absorption

process


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Dose

Cp

absorption

distribution

elimination

EFFECT


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Distribution Kinetics

Rate and extent of distribution from vascular fluid totissue space

Determinants of equilibration rate

Blood flow Determinants of equilibrium gradient

Tissue factors

Vascular permeability

Macromolecular binding in plasma and tissue

Physicochemical factors MW, lipophilicity, affinity for carriers


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Sinusoids of the Liver


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Tissue Perfusion Rates

(ml/min-100g tissue )High

Lung 400

Kidney 350

Liver 85Brain 55

Intermediate/variableSkeletal muscle 5

LowFat 3


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Binding Sites in Plasma

PROTEIN MW CONCENTRATION

albumin 67,000 500-700 uM

a1-acidglycoprotein

42,000 9-23 uM


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Plasma Protein Binding

DRUG

PERCENT BOUND

IN PLASMA

Warfarin 99%

Codeine 7%


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Fluid Compartments

70-kg AdultCompartment Liters %BW Indicator

plasma 3 4 131I-albumin

extracellular water 12 17 sucrose

total body water 41 58 D2O


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Apparent Volume of Distribution

VD

Volume of the body into which thedrug appears to have distributed


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Concentration = Amount

Volume


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amount in body (grams)volume (liters)

= plasma concentration Cp (g/l)

Vd as Determinant of Cp


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Onecompartment

Twocompartment

Katzung, 2001


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Drug Structure and Vd

High MW such as proteins Vd about plasma volume, 4% BW

Small MW and polar Vd about extracellular fluid volume, 17% BW

Small MW and lipophilic

Vd about total body water, 58% BW even larger if highly lipophilic and

accumulates in fat, >> 58% BW


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Elimination Kinetics

Rate and extent of elimination byexcretion or biotransformation

Quantitation by total clearance (ClT)

Volume of plasma cleared of compound

per unit time by all routes and mechanisms Expressed as ml/min or ml/hr

Cl d Bl d Fl


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Clearance and Blood Flow

organ

Cp arterialCp venous

Cl organ = ( blood flow ) (Cpa-Cpv) / Cpa


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Total Clearance

Relates Cp to Elimination Rate

( ClT ) ( Cp ) = dA / dt


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Drug Elimination

Parent

compound

Metabolite

Excretion

Excretion

Furthermetabolism

ClR

ClNR


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Total Clearance

Is sum of renal and nonrenal clearances

ClT

= ClR

+ ClNR

Renal refers to urinary excretion unchanged

Nonrenal refers to all other routes and

mechanisms


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Nonrenal Clearance

Excretion unchanged

Lungs (if high vapor pressure)

Bile

Biotransformation

Phase I oxidation, reduction, hydrolysis

Phase II conjugations


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Significance of Biotransformation

Prodrug Active Drug

Metabolite 1 Metabolite 2 Metabolite 3

(inactive) (active) (toxic)


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Kinetics of Biotransformation

Enzymatic reactions and thereforeMichaelis-Menton kinetics

Generally therapeutic levels


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Exceptions to First-Order Kinetics

Drugs where therapeutic level >> Km Ethanol

Aspirin

Toxic levels may exceed Km Acetaminophen


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Causes of Variability inClearance by Biotransformation

Exposures

Genetics

Age

Disease


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Pathways of Biotransformation

Drug

phase 1Metabolite

phase 2Conjugated Metabolite


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Phase 1

Cytochrome P450 Enzymes Heme containing

Imbedded in membrane of smoothendoplasmic reticulum (microsomes)

Highest activity in liver

Catalyze addition of molecular oxygen


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CYP450 Family

About 17 human genes

Promoters include certain drugs,

herbal medicines and environmentalchemicals

Isozymes differ in substrate specificity,

promoters, and inhibitors


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Inducers of CYP450 Isozymes

INDUCER ISOZYME

Cigarettesmoke

(PAHs)

CYP1A1

Barbiturates CYP2B

Steroids CYP3A4


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Phase II Conjugating Moieties

Glucuronic Acid

Sulfate

Methyl Groups

Glutathione

Acetyl Groups

Glycine


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Sites of Morphine

Biotransformation


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Renal Clearance

Volume of plasma cleared by excretionunchanged into urine

Mechanisms Glomerular filtration of unbound low MW

drug

Proximal tubular secretion, mediated by

carrier proteins such as oatp, mdr Passive reabsorption of uncharged,

lipophilic drug


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Mechanisms of Renal Clearance

Glomerular filtration

Proximal tubular secretion

Reabsorption


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Determination of ClR

ClR = Urinary excretion rate / Cp

ClR = Amount excreted duringcollection interval / interval length

/ Cp at midpoint of interval


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Relationship of ClR to Mechanism ofRenal Excretion

ClR Mechanismml/min/70 kg

0-120 exclusion from filtration and/ornet reabsorption

120 (GFR) glomerular filtration and noreabsorption

120-640 (RPF) glomerular filtration and net tubularsecretion

2a-c imp walsh drug transport, absorption 2011

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