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