Pharmacokinetics

Component Processes

Absorption – entry of a drug from its site of administration to the systemic circulation

Distribution – process by which a drug enters the interstitium or tissues from the blood

Metabolism / Biotransformation – processes by which a drug is changed: to its active form or to its removable form

Excretion – removal of the drug from the body

Drug

ABSORPTION into Plasma

DISTRIBUTION to Tissues

Bound Drug

Free Drug

Tissue Storage

Sites of Action

Drug METABOLISM: Liver, Lung, etc

Drug EXCRETION: Renal, Biliary, etc.

Drug Biodisposition / Pharmacokinetics

Permeation

Permeation – travel of a drug across cellular membranes, influencing its biodisposition; is dependent on:SolubilityIonization Concentration gradientSurface areaTissue vascularity

Drug PermeationSolubility

Lipid solubility – ability to pass through lipid bilayersWater solubility – in aqueous phasesPartition coefficient – ratio of lipid to aqueous solubility : the higher

the partition coeff, the more membrane soluble the drug Ionization

The Henderson–Hasselbach equation – determines the percentage of ionization (ionized=water-soluble; nonionized=lipid-soluble)

Drugs are either weak acids or weak bases, & can exist as charged or neutral particles in equilibrium, depending on pH & pKa

Ionization increases renal clearance of drugs

Drug Permeation

Concentration gradient – diffusion is down a concentration gradient; the greater the concentration gradient, the faster the diffusion/permeation

Surface area – the available area for permeation; the greater the surface area, the faster the diffusion / permeation

Tissue Vascularity – density of blood supply & speed of blood flow – the better/more the tissue vascularity, the better the permeation

AbsorptionPassive diffusion – most common

Aqueous diffusion: Fick’s Law:

Flux (J) = (C1 – C2) x S.A. x P. coefficient

Thickness J = molecules per unit time C1= higher concentration C2 = lower concentration S.A. = surface area available for diffusion P. Coefficient = permeability coefficient / partition coefficient Thickness = length of the diffusion path

Absorption

Lipid diffusion: the Henderson–Hasselbalch equationlog (protonated / unprotonated) = pKa – pH

*for acids: pKa = pH + log x concentration [HA] unionized concentration [A] *if [A] = [HA], then pKa = pH + log (1); log (1) = 0, so

pKa = pH

*for bases: pKa = pH + log x concentration [BH+] ionized concentration [B]

*if [B] = [BH+], then pKa = pH + log (1); log (1) = 0, so pKa = pH

weak Acids & weak Bases A weak acid is a neutral molecule that dissociates

into an anion & a proton (H+) so that its protonated form is neutral, more lipid-soluble

A weak base is a neutral molecule that can form a cation by combining with a proton so its protonated form is charged, water-soluble

weak acids pKa weak bases pKa

Phenobarbital 7.1 Cocaine 8.5

Pentobarbital 8.1 Ephedrine 9.6

Acetaminophen 9.5 Chlordiazepoxide

4.6

Aspirin 3.5 Morphine 7.9

Diffusion

Aqueous diffusionwithin large aqueous

compartments across tight junctions across endothelium thru

pores (MW20,000 - 30,000)molecules tend to move

from an area of higher to an area of lower concentration

plasma protein-bound drugs cannot permeate thru aqueous pores

charged drugs will be influenced by electric fields

Lipid diffusion higher partition coefficient =

easier for a drug to enter lipid phase from aqueous

charged drugs – difficulty in diffusing thru lipid

uncharged – lipid-soluble lower pH relative to pKa,

greater fraction of protonated drug (protonated form of an acid is neutral; protonated form of a base is charged)

A weak acid at acid pH & a weak base at alkaline pH will be more lipid-soluble

Carrier – mediated Transport

Facilitated diffusion – passive (no E expended) carrier-mediated transport.saturable; subject to competitive & non-competitive inhibitionused by peptides, amino acids, glucose

Active (uses E) carrier-mediated transportsaturablesubject to competitive & non-competitive inhibitionagainst a concentration gradient e.g. Na – K pump

Endocytosis & Exocytosis

ENDOCYTOSIS entry into cells by very large substances

(uses E) e.g. Iron & vit B12 complexed with their

binding proteins into intestinal mucosal cells

EXOCYTOSIS expulsion of substances from the cells

into the ECF (uses E) e.g. Neurotransmitters at the synaptic

junction

Ion TrappingIon trapping or reabsorption – delays

excretionKidneys:

nearly all drugs are filtered at the glomerulus most drugs in a lipid-soluble form will be reabsorbed by

passive diffusion to increase excretion: change urinary pH to favor the charged

form of the drug (not readily absorbed)– weak acids are excreted faster in alkaline pH (anion form favored)– weak bases are excreted faster in acidic pH (cation form favored)

Other sites: body fluids where pH differs from blood pH, favoring trapping or reabsorption

stomach contents ▪ aqueous humor small intestines ▪ vaginal secretions breast milk ▪ prostatic secretions

DistributionFirst pass effect – decreased bioavailability

of drugs administered orally because of initial absorption into the portal circulation & distribution in the liver where they may undergo metabolism or excretion into bile

Extraction Ratio – magnitude of the first pass effect. ER = cl Liver / q (hepatic blood flow)

Systemic drug bioavailability – determined from extent of absorption & ER.F = f x (1 – ER)

Distribution

Volume of Distribution – ratio between the amount of drug in the body (dose given) & the concentration of the drug in blood plasma. Vd = drug in body / drug in blood

Factors influencing Vd: drug pKa (permeation)extent of drug-plasma protein bindinglipid solubility (partition coefficient)patient age, gender, disease states, body composition

Drug – Plasma Protein Binding

Most drugs are bound to some extent to plasma proteins Albumin, Lipoproteins, alpha 1 acid glycoprotein

Extent of protein binding parallels drug lipid solubility

Binding of drug to Albumin is often non-selective,

Acidophilic drugs bind to Albumin, basophilic drugs bind to Globulins

drugs with similar chemical/physical properties may compete for the same binding sites

Volume of distribution is inversely proportional to protein binding

Distribution Non-ionized (hydrophobic) drugs cross

biomembranes easilyBinding to plasma proteins accelerates

absorption into plasma but slows diffusion into tissues

Unbound / free drug crosses biomembranesCompetition between drugs may lead to

displacement of a previously bound drug higher levels of free/unbound drug better distribution

Distribution occurs more rapidly with high blood flow & high vessel permeability

Distribution Special barriers to distribution:

placenta blood-brain barrier

Many disease states alter distribution: Edematous states – cirrhosis, heart failure, nephrotic syndrome –

prolong distribution & delay ClearanceObesity allows for greater accumulation of lipophilic agents within

fat cells, increasing distribution & prolonging half-lifePregnancy increases intravascular volume, thus increasing

distribution hypoAlbuminemia allows drugs that normally bind to it to have

increased bioavailabilityRenal failure may decrease drug bound fraction (metabolite

competes for protein binding sites) & thus ↑ free drug levels

Blood Brain Barrier (BBB): Only lipid-soluble compounds get through the BBB. Four components to the blood-brain barrier:

Tight Junctions in brain capillaries Glial cell foot processes wrap around the capillaries Low CSF protein concentration ------> no oncotic pressure for

reabsorbing protein out of the plasma. Endothelial cells in the brain contain enzymes that metabolize,

neutralize, many drugs before they access the CSF. – MAO and COMT are found in brain endothelial cells. They

metabolize Dopamine before it reaches the CSF, thus we must give L-DOPA in order to get dopamine to the CSF.

Exceptions to the BBB. Certain parts of the brain are not protected by the BBB: Pituitary, Median Eminence Supraventricular areas Parts of hypothalamus

Meningitis: It opens up the blood brain barrier due to edema. Thus Penicillin-G can be used to treat meningitis (caused by Neisseria meningitides), despite the fact that it doesn't normally cross the BBB. Penicillin-G is also actively pumped back out of the brain once it has crossed the BBB.

Sites of Concentration: can affect the VdFat, Bone, any Tissue, Transcellular sites: drug concentrates in

Fat / Bone / non-Plasma locations lower concentration of drug in Plasma higher Vd

MetabolismBiotransformation of drugs (usually in the Liver;

also in the Lungs, Skin, Kidney, GIT)) to more polar, hydrophilic, biologically inactive molecules; required for elimination from the body.

Phase I reactions – alteration of the parent drug by exposing a functional group; active drug transformed by phase I reactions usually lose pharmacologic activity, while inactive prodrugs are converted to biologically active metabolites

Phase II reactions – parent drug undergoes conjugation reactions (to make them more soluble) that form covalent linkages with a functional group: glucuronic acid, acetyl coA, sulfate, glutathione, amino acids, acetate, S-adenosyl-methionine

Metabolism Phase I reaction products may be directly excreted in

urine or react with endogenous compounds to form water-soluble conjugates

mixed function oxidase system (cytochrome P450 enzyme complex: Cyt P450 enzyme, Cyt P450 reductase) requires NADPH (not ATP) as E source, & molecular O2; [drug metabolizing enzymes are located in hepatic microsomes: lipophilic, endoplasmic reticulum membranes (SER)]

Phase I enzymes perform multiple types of reactions:

OXIDATIVE REACTIONS REDUCTIVE REACTIONS HYDROLYTIC REACTIONS

CYTOCHROME-P450 COMPLEX: There are multiple isotypes.

CYT-P450-2, CYT-P450-3A are responsible for the metabolism of most drugs. CYT-P450-3A4 metabolizes many drugs in the GIT, decreasing the

bioavailability of many orally absorbed drugs. INDUCERS of CYT-P450 COMPLEX: Drugs that

increase the production or ↓ degradation of Cyt-P450 enzymes. Phenobarbital, Phenytoin, Carbamazepine induce CYT-P450-3A4 Phenobarbital, Phenytoin also induce CYT-P450-2B1 Polycyclic Aromatics (PAH): Induce CYT-P450-1A1 Glucocorticoids induce CYT-P450-3A4 Chronic Alcoholism, Isoniazid induce CYT-P450-2E1. important! this drug

activates some carcinogens e.g. Nitrosamines. *Chronic alcoholics have up-regulated many of their CYT-P450 enzymes.

INHIBITORS of CYT-P450 COMPLEX Inhibit production: Ethanol suppresses many of the CYT-P450

enzymes, explaining some of the drug-interactions of acute alcohol use.

Non–competitive inhibition: Chloramphenicol is metabolized by Cyt P450 to an alkylating metabolite that inactivates Cyt P450

Competitive inhibition: Erythromycin inhibits CYT-P450-3A4. Terfenadine (Seldane) is metabolized by CYT-P450-3A4, so the toxic unmetabolized form builds up in the presence of Erythromycin. The unmetabolized form is toxic and causes lethal arrhythmias. This is why Seldane was taken off the market;Cimetidine, Ketoconazole – bind to the heme in Cyt P450, decreasing metabolism of Testosterone & other drugsSteroids: Ethinyl estradiol, Norethindrone; Spironolactone; Propylthiouracil (PTU): inactivate Cyt P450 by binding the heme

MetabolismPhase II Drug Conjugation reactions: “detoxification”

rxns: non-microsomal, primarily in the liver; also in plasma & GIT – usually to glucuronides, making the drug more soluble.

conjugates are highly polar, generally biologically inactive (exception: morphine glucuronide – more potent analgesic than the parent compound) & tend to be rapidly excreted in urine or bile

“Enterohepatic recirculation”: high molecular weight conjugates are more likely to be excreted in bile intestines, where N flora cleave the conjugate bonds, releasing the parent compound into the systemic circulation delayed parent drug elimination & prolongation of drug effects

conjugation, hydrolysis, oxidation, reduction

Reaction Reactant transferase substrate Example

Glucuron-idation

Glucuronic acid

Glucuronyl transferase

Phenols, alcohols, carbolic acids, hydroxylamines, sulfonamides

Morphine acetaminophen diazepam digitoxin meprobamate

Acetylation Acetyl CoA N-Acetyl-transferase

Amines Sulfonamides isoniazid clonazepam dapsone mescaline

Glutathione conjugation

Glutathione GSH- S-transferase

Epoxides, nitro groups, hydroxylamines

Ethacrynic acid bromobenzene

Reaction Reactant transferase substrate Example

Sulfate conjugation

Phospho-adenosyl phospho-sulfate

Sulfo-transferase

Phenols, alcohols, aromatic amines

Estrone warfarin acetaminophen methyldopa

methylation S-adenosyl methionine

Trans-methylases

Catecholaminesphenols, amines

Dopamine epinephrine histamine thiouracil, pyridine

Toxicity

drugs are metabolized to toxic products

hepatotoxicity exhibited by acyl glucuronidation of NSAIDSN-acetylation of IsoniazidAcetaminophen in high doses – glucuronidation & sulfation

are usual conjugation reactions in therapeutic doses, but in high doses, these get saturated so Cyt P450 metabolizes the drug, forming hepatotoxic reactive electrophilic metabolites fulminant hepatotoxicity & death (antidote: N-acetylcysteine)

Reduction in Bioavailability

First pass effectIntestinal flora metabolize the drugDrug is unstable in gastric acid e.g.

PenicillinDrug is metabolized by digestive

enzymes e.g. InsulinDrug is metabolized by intestinal wall

enzymes e.g. sympathomimetic drugs / catecholamines

Excretion Clearance – CL – removal of drug from the blood,

or the amount of blood/plasma that is completely freed of drug per unit time over the plasma concentration of the drug

CL = rate of elimination of drug plasma drug concentration

especially important for ensuring appropriate long-term dosing, or maintaining correct steady state drug concentrations

Renal clearance - unchanged drug, water-soluble metabolites – glomerular filtration, active tubular secretion, passive tubular reabsorption of lipid-soluble agents

Hepatic clearance – extraction of drugs after GIT absorption

Excretion

KIDNEY GLOMERULAR FILTRATION: Clearance of the apparent volume

of distribution by passive filtration. Drug with MW < 5000 ------> it is completely filtered. Inulin is completely filtered, and its clearance can be

measured to estimate Glomerular Filtration Rate (GFR). TUBULAR SECRETION: Active secretion.

Specific Compounds that are secreted: – para-Amino Hippurate (PAH) is completely secreted, so its

clearance can be measured to estimate Renal Blood Flow (RBF).

– Penicillin-G is excreted by active secretion. Probenecid can be given to block this secretion.

Excretion

Half life (t ½) – time required to decrease the amount of drug in the body by 50% during elimination or during a constant infusion; useful in estimating time to steady-state: approximately 4 half-lives to reach

94% Estimation of time required for drug removal from the body Estimation of appropriate dosing interval: drug accumulation occurs

when dosing interval is less than 4 half-livesAffected by Chronic renal failure – decreases clearance, prolongs half-life increasing Age – Vd changes, prolongs half-life Decreased plasma protein binding shortens half-life

Half – Life

The half-life is inversely proportional to the Kel, constant of elimination. The higher the elimination constant, the shorter the half-life.

Drug Elimination

Zero order kinetics – rate of elimination of the drug is constant regardless of concentration i.e. constant amount of drug eliminated per unit time so that concentration decreases linearly with time

examples: ethanol, phenytoin, aspirinFirst order kinetics – rate of elimination of the

drug proportional to concentration i.e. constant fraction of the drug eliminated per unit time so that concentration decreases exponentially over time

that’s all for now. . .