drug absorption, distribution, metabolism, elimination chapter 3
TRANSCRIPT
Drug Absorption, Distribution, Metabolism,
EliminationChapter 3
Physical/Chemical Properties of Drugs
Ability to Approach Receptors
Drug Mol’s Receptors
• Bloodstream (cardiovascular system)– Bulk flow transfer– Fast, long-distance– Chem nature of drug not impt
• Short distances– Diffusion– Chem properties impt
Chem Properties Impt to Diffusion
• Aqueous diffusion delivers most drug mol’s
• Rate of diffusion dependent on molec size– Diffusion coeff = 1/ MW– BUT: Most drugs 200-1000 MW, so little
difference
• Ability to cross barriers– Cell membr’s mostly lipid– Drug hydrophobicity impt
Absorption = Movement Across Cell Barriers
• Cell membr’s separate aqueous compartments– Movement through cell involves
traversing at least 2 lipid bilayers• Some tight junctions between cells
– Ex: CNS, placenta, testes• Some freely permeable
– Ex: Liver, spleen• Vascular endothelium differs in
permeability
Small Mol’s Cross Cell Membr’s
• Diff’n lipid• Diff’n
aqueous pores traversing lipid bilayer– BUT most pores
too small to accomm most drugs
• Transmembr carrier prot
• Pinocytosis– Not impt for
small mol’s
Diffusion
• Number mol’s crossing membr per unit area in unit time; depends on
• Permeability coefficient (P)– Diffusivity
• Diffusion coefficient• Doesn’t differ much between drugs
– Solubility in membr• Partition coefficient (solubility oil/solubility
water)• Most impt to pharmacokinetics• Used as predictor of drug properties
secobarbital thiopentalbarbital
pH and Ionization
• Many drugs are weak acids/bases– Can be ionized, unionized – Varies w/ pH of environment
• Acids release H+– Strong: All H+ released– Weak: Some H+ released
• Ka quantitates strength of acid
• Weak acid ionization (HA H+ + A-)– Ka = [H+][A-]/[HA]– Negative log and rearrangement:
• Log [H+] = log Ka + log [A-]/[HA]
– pH = pKa + log [A-]/[HA]• Henderson/Hasselbach equation• pKa = pH when drug 50% dissoc’d
• Weak base ionization (BH+ H+ + B)– Ka = [H+][B]/[BH+]– Negative log and rearrangement– pH = pKa + log [B]/[BH+]
• Rearrangement if known pH, pKa allows deter’n ionized/unionized ratio at any pH environment
pH Differences between Body Compartments
• Environmental pH effects ability to release H+ (ionization)
• Ionized species have low lipid solubility– Most: uncharged can traverse cell membr’s
• So each environment’s pH effects drug dist’n between them– Ion trapping Compartment equilibrium
Ex: Stomach Blood
• Assume weak acid drug (HA) w/ pKa=6.0• Assume [HA]=1.0• Stomach pH=1.0
– 1.0-6.0=log [A-]/[HA]– 1.0x10-5=[A-]
• Little ionized drug
• Blood pH=7.0– 10=[A-]
• Much ionized drug
• Expect stomach-to-plasma traverse BUT not plasma-to-stomach
Book ex: more basic drug (how do we know?) Plasma Digestive Tract
• Acidic drugs concent’d in high pH compartment– Site of highst dissoc’n H+ (ionization)– Can’t traverse membr to escape
• Basic drugs concent’d in low pH environment
• Largest pH between compartments largest [drug]– BUT not total impermeability– AND not total equilib– Most impt to gi, renal
Carrier Mediated Transport
• Specialized for physiologically impt mol’s– Sugars, neurotransmitters, metals, etc
• Transmembr prot– Binds mol(s)– Changes conform’n– Releases to other side of membr
• Diff kinetics than simple diffusion– Can become saturated– Subject to competition between ligands
• Two types of carriers allow– Facilitated diff’n
• Along concent gradient
– Active transport• Against gradient• Cell uses chem energy
• Carriers impt pharmacologically– Renal tubule– Biliary tract– Blood-brain barrier– GI tract
• P-glycoprotein impt drug transporter– Renal tubular cells, bile canaliculi, brain
microvessels
Drug Administration
Two Major Routes• Internal
– Via gastrointestinal tract (gi)• Oral• Sublingual• Buccal
• Parenteral– Via injection
• IV• IM• Subcu• Intrathecal
Oral Administration
• Convenient; includes most drugs• Little absorption until small intestine
– Are most drugs weak acids or bases?
• Abs’n from small intestine– Passive transfer dependent on
• Ionization• Lipid solubility
– Some carrier-mediated transport• Levodopa through carrier for phenylalanine• Fluorouracil through carrier for pyrimidines• Fe, Ca
• Rates abs’n after oral admin depend on– Gi motility
• Some disorders gastric stasis• Some drugs affect motility (incr or decr)• Meals
– Splanchnic blood flow– Drug particle size/formulation
• Capsules/coated tablets• Timed release formulations
– Physicochemical factors• Tetracycline binds Ca milk prevents abs’n• Drug interactions
Bioavailability
• Proportion of drug that passes into systemic circ’n after oral admin
• Dependent on– Absorption– Local metab by small intestine enzymes
• Indiv pts’ physiology impt– Activity intestinal metab enz’s– pH variations– Motility
• Differs w/ type dose (oral, IV)– Oral dosing further metab
• Book: First pass effect through liver
– = AUCoral/AUCIV x doseIV/doseoral
• AUC = Area Under Curve of drug plasma concent vs. time
• “Bioequivalence” used to compare generic drugs to patented
Other Types of Drug Admin
• Sublingual – Impt when
• Rapid response req’d• Drug unstable at gastric pH• Drug rapidly metab’d by liver
– Pass straight into systemic circ’n• Don’t enter liver portal system (so no first-
pass effect)
• Ex: glyceryl trinitrate relieves angina– Metab NO release– NO act’s soluble guanylate cyclase (sim
to ad cyclase) incr’d cGMP act’n prot kinase G biochem cascade in smooth muscle dephosph’n myosin light chains,
sequestering Ca vascular smooth muscle relaxation
• Also relaxes cardiac muscle decr’d bp, so red’d preload, cardiac
afterload• So decr’d cardiac O2 consumption
– Also redist’n coronary blood flow toward ischemic cardiac areas
• Rectal– Abs’n unreliable– Often for local action– Useful in pts vomiting, unable to take by
mouth (infants)
• Cutaneous– Local effect on skin req’d– Abs’n occurs systemic effects– Suitable for lipid-soluble mol’s– Ex: estrogen patch
• Nasal sprays– Abs’n through mucosa overlaying
lymphoid tissue– Impt for drugs inact’d in gi– Ex: peptide hormone analogs, ADH,
calcitonin• Inhalation
– Large surface area and high blood flow– No gi inact’n– BUT also route of elim’n– Ex: volatile, gaseous anesthetics– Ex: locally acting drugs– Ex: inhaled human insulin being tested
Admin by Injection• Subcutaneous, intramuscular
– Faster than oral– Rate abs’n depends on site admin, local
blood flow– Red’n or prolonging systemic action poss
by altering drug mol or prep’n or giving w/ another agent
• Intrathecal– Into subarachnoid space via lumbar
puncture– Ex: regional anesthetics– Ex: cancer chemotherapeutics– Ex: antibiotics for NS infections
• Intravenous (IV) fastest, most certain– Bolus high concent R heart, lung,
systemic circ’n– Peak concent depends on rate injection– Common ex: antibiotics, anesthetics– Most uncomplicated to understand
distribution, pharmacokinetics
Distribution of Drugs in the Body
Pharmacokinetics
Experimental Finding
• Rates drug abs’n, dist’n, elim’n gen’ly directly proportional to physio concent
• First order kinetics– Rate varies w/ first power of concent dC(t)/dt = -kEC(t)
where dC(t)/dt = rate change [drug] kE = elimination constant
(neg sign due to decr [drug] w/ elim’n)
• Note: rate elim’n may be zero order (independent of concentration)– Ex: ethanol
Kinetics Meas’d w/ Single IV Dose
• Single bolus over 5-30 sec• Periodic blood samples analyzed for
[drug]– Time ~0 – highest concent
• Dist’n drug in circulation equilib• Complete by sev passes through heart (sev min)
– Later time – concent decr’s due to• Dist’n tissues• Dist’n other body fluids• Metab other cmpds• Excr’n unchanged drug (renal, biliary, lung)
• (Concent (y axis) reflects free drug + drug bound to plasma prot’s)
• Conversion to log concent more linear curve– Non-linear portion
– dist’n phase ( phase)
• Rapid decr plasma concent
– Linear portion – elimination phase ()
• Grad decr plasma concent
• Eq’n line for elim’n phase: C(t) = C0e-kEt
– Where C(t) = Concent drug @ time (t) C0 = Concent @ time 0
e = nat’l log base kE = rate const for phase
(elim’n rate const)
t = time
– Y int = C0; slope = -kE/2.3
• Can be used to deter rate dist’n when phase included
With Oral Admin…• Plot differs in phase• Initial: [plasma] = 0
– Swallowing, dissolution, abs’n take time
• Rapid abs’n rate phase incr’s – First order: rate incr w/ incr’d [drug]
• Peak concent at rate abs’n = rate elim’n
Body Fluid Compartments: Sites of [Drug]
• Total body water=50-70% total body wt
• Intracell highest• Extracell:
– Interstitial = between cells– Plasma = blood + lymph– Transcell = cerebrospinal, intraocular,
synovial, etc.• Fat is also compartment
– BUT poorly perfused
• Dug mol’s exist ionized/unionized, free/bound in each compartment
• Dist’n pattern for each drug dependent on– Membrane permeability/transport– Binding w/in compartment– pH partitioning– Fat/water partitioning
Specialized Compartment – Blood Brain Barrier
• History: Ehrlich -- dyes injected IV stained most tissues; brain unstained
• Contin layer endothelial cells w/ tight junctions– Non-brain – fenestrations
• Specific transport for small organics• Safety buffer• Throughout brain, spinal cord
– Except floor of hypothal, area postrema
• Inaccessible to many drugs unless high lipid solubility– BUT inflamm’n can disrupt integrity– AND some peptides increase bbb
permeability– Intrathecal injection sometimes
circumvents
Volume of Distribution
• Vol fluid req’d to contain drug in body at same concent as that present in plasma
• May indicate drug binding to plasma prot or other tissue constituents
• Vd = D/C0
– Where Vd = vol dist’n (L)
D = dose w/ IV injection (mg)C0 = blood concent @ 0 time
(mg/L)
• Most impt: free drug in interstitial fluid
• Drug values vary greatly– Molecular
wt– More impt:
binding plasma prot’s
Drug Binding to Plasma Proteins
• Reflected in Vd
• If high binding, drug “trapped” in plasma– High C0 on graph (Y reflects bound +
unbound drug)– For Vd=D/C0, Vd very low (2-10L)
• Ex: warfarin (anticoagulant)
• If low binding, drug free to disperse tissues– Low plasma concent (= low C0)– Vd high (40,000 L)
• Ex: furosemide (diuretic)
• Plasma proteins that bind drugs– Albumin impt to acidic drugs
• Most abundant plasma prot– Not fully saturated
• Synth’d in liver• Concent changes w/ disease, dysfunction
-acid glycoprotein impt to basic drugs• Lower concent than albumin• Varies among population• Varies in individual if disease states
– Lipoprotein binding not well understood• Varies w/ disease states
Clearance
• Vol blood cleared of drug per time• Describes efficiency of elim’n from
body– Sum of all types elim’n
• Renal• Hepatic• Organ
• Impt; independent of– Vol dist’n– Bioavailability– Half-life
• Elim’n rate – quantity of drug removed– Assume first order kinetics
• CLp = rate elim’n drug/plasma [drug]
Where CLp = total body removal from
plasma (p) (mL/min), when rate elim’n (mg/min) plasma concent (mg/mL)
• Useful clin’ly for dosage rate, if target concent known
• Time nec for [drug] to decr by half• Can be found from graph log C(t) vs. t
where C(t) = concent drug @ time t
• Mins – days• Impt to deter’n multiple dosing
regimen• Dependent on clearance, vol dist’n
t1/2 = (0.693 x Vd)/CL
Half-Life (t1/2)
Drug Metabolism
Biotransform’n Drug Molecules
• Drug changed chem’ly metabolite– Prodrugs must be metab’d for act’n
• Chem alteration by enz rxn• Gen’ly nonpolar, lipid-sol cmpds
more polar, water-sol– Now easier urinary excr’n
• Some metabolites active (or more active) than parent drugs– Ex: demethlyation diazepam (less)
active agent but w/ longer ½ life than parent
• Drug metabolizing enz’s mostly in liver• BUT most other tissues also can
metabolize– Lung– Kidney– Gi– Placenta– Gi bacteria
• Four impt types chem rxns for drug metab– Oxidation– Reduction– Conjugation– Hydrolysis
• Ox’n, conjugation most impt• Partic enz’s carry out these rxns
Two Major Metabolism Types
• Phase I Reactions– Catabolic
• Mostly ox’ns
– Functionalization: • Intro reactive grp (ex: hydroxyl)• Prod’s more chem’ly reactive, hydrophilic
than parent• Serves as pt chem attack for….
• Phase II Reactions– Anabolic (synthetic)– Involve conjugations rxns
• Attachment substituent• Large, hydrophilic
• Liver major site Phase I, II rxns– Metabolic enz’s embedded in smooth ER
• Microsomal• Stereoselective
• Both types rxns more polar, hydrophilic metabolites
Phase I Rxns• Catalyzed by Cytochromes P450 (CYP’s)
– Enz superfamily • 74 CYP gene families• Differ in aa seq, inhibitors/inducers, specificity
– 3 main families impt to hepatic drug metab (CYP’s 1, 2, 3)
• CYP1A2 – a main enz
– Contains heme w/ Fe• Redox capability
• Binds O2
– Assoc’d w/ NAD(P) reductase enz
• Allows metab many diff agents• Most common to all substrates: lipophilicity
• Gen’l rxn: DH + NAD(P)H + H+ + O2
DOH + NAD(P)+ + H2O
where DH = drug NAD(P)H = red’d coenzyme DOH = ox’d drug NAD(P)+ = ox’d coenzyme O2 = final electron acceptor
• Complicated cycle results in 1 O atom added to drug, other O water– Free radical or iron-radical grps formed at
parts of cycle• Highly reactive, dangerous
Fp = Flavin Protein Coenzyme (NADPH-P450 Reductase)
• Other metabolic rxns (some enz catalyzed) include red’n, hydrolysis– Alcohol dehydrogenase metab’s ethanol– Monoamine oxidase metab’s many amines
• Some foods, other drugs, herbs, environmental agents, inhibit/induce CYP’s change in metabolism drugs change drug activity– Grapefruit juice, St. John’s wort inhibit
drug metab by inhib’n CYP enz’s– Brusssels sprouts, cigarettes induce
P450 enz’s
Phase II Reactions
• Attachment substituent grp on parent/ metabolite– Typically added @ hydroxyl, thiol, amino– Substituent first “activated”
• Phosph’n• Att’d to CoA• S-Adenosyl methionine
• Rxn enzyme-catalyzed• Product almost always inactive, less
lipid soluble– Excr’d in urine, bile
• Common conjugated substituents– Glucuronyl– Sulfate– Methyl– Acetyl– Glycyl– Glutathione
Rates of Drug Metab
• Follow MM kinetics– V = (Vmax[S])/KM + [S]
• In vivo, Vmax directly proportional to [enz]– Can have competition between drugs
metab’d by same enz– BUT most drugs found at concent’s <<
KM so far below saturation of enz active sites
• Enzyme induction – synth of metabolic enz’s stimulated– Both microsomal and conjugating
systems– See incr’d metabolic activity
• Due to repeated exposure to– Drugs– Environmental chem’s– Carcinogens
• May decr’d drug activity OR incr’d activity
Figure 3-10 Example of enzyme induction. Zoxazolamine administered by intraperitoneal injection to rats. For induction studies, phenobarbital or 3,4-benzo[a]pyrene was injected twice daily for 4 days before injection of zoxazolamine.
• Most thoroughly studied inducers – PAH’s (env chem’s also found in cigarettes)– Lipophilic– Bind nuclear receptors (Ah receptors)– Complexes bind response elements on DNA Promotion transcr’n CYP1A1 gene
• Book: Induction P450s by PAHs in cigarette smoke decr’d estradiol in female smokers
First Pass Effect of Liver
• Liver site of much metab– Amt abs’d >>> amt reaching systemic
circ’n– Impt to many drugs
• Much give much larger oral dose than needed
• Indiv variations in extent of first-pass effect for partic drugs among population (so unpredictability)
Biliary Excr’n
• Liver may excrete drugs bile– Drug carrier system (P-glycoprotein) impt
• Bile duct carries small intestine• Glucuronides concent’d in bile
– At small intestine, enz’s cleave glucuronide active drug released, reabs’d
– Cycle repeated – “Enterohepatic circulation” “reservoir” of recirculating drug
Elimination from the Body
Renal Elimination
• Kidney clears some drugs very efficiently (penicillin in single pass), others take many passes through renal tubule for excr’n
• Glomerular filtration– ~20% renal plasma flow filtered through
glomerulus– MW < 20000 diffuse into glomerular filtrate– Appreciable binding to albumin decr’d
diffusion into filtrate
• Tubular secretion– ~80% renal blood flow passes through
peritubular capillaries of prox tubule– Two carriers transport drugs from blood
in capillaries proximal renal tubule• Carrier for acidic mol’s (including endogenous
acids)• Carrier for basic mol’s• Move against electrochem gradient
– Can achieve max drug clearance– Movement of free drug mol’s out of
plasma pushes equilib toward freeing drug mol’s from albumin more free drug elim’d and more drug dissoc’ng from albumin
• Diffusion across renal tubule– Most water reabs’d from renal tubule
• Concentrates urine
– Highly lipophilic drugs can move across tubule cell membr’s, reabs’d back into blood
– Highly polar drugs (low permeability) remain in tubule
– pH change in urine ionization ion trapping in urine elimination• Basic drugs more rapidly excr’d in acidic
urine
One-Compartment Model• Simplest kinetics• Volume of distribution considered
single, well-stirred compartment
Real Life is More Complicated…
Two Compartment Model
• Add repeated doses, saturating kinetics, other physiological parameters: kinetics more difficult