Module 4
Pharmacokinetics
By Lauren McCormick

Absorption

Distribution

Metabolism

Excretion

Where? From the site of administration

Where? Within the body to organs and tissues

What? Biotransformation of drug, often inactivating

What? Removal of drug or drug metabolite from the body

What? Drug movement across cell barriers

How?

Passive movement

Active transport

Majority: non-specific diffusion

Majority of the rest: specific carrier

Small water soluble molecules: aqueous pores

Pinocytosis: large molecules

Diffusion through lipid membranes

lipid solubility determines how well & how much of a drug passes through membrane

experimentally determined

partition co-efficient: ratio of drug dissolving in oil/water

too lipid soluble --> will not pass through lipid membrane

pH & ionization

weak acid/weak base drugs

ionized or uncharged depending on pH of surrounding environment

ionized drugs dissolve well in aqueous fluids

uncharged drugs more easily pass through lipid membranes

knowing pKa & pH

estimate what proportion of drug will be ionized & therefore how much of the drug will cross lipid membrane

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pH differences

gradients of drug accumulation

weakly acidic aspirin accumulates in compartments w/ high pH

weakly basic pethidine/mepiridine tends to accumulate in compartments of low pH

Organic cation/anion transporters

Solute Carriers (SLC)

passive movement of solutes down gradients

structurally related Organic Cation Transporter (OCT) & Organic Anion Transporter (OAT)

imporant for transfer at BBB, GIT, renal tubule

specialized transporter complexes

mediate cell uptake & movement across membranes

electrochemical gradient

ATP-binding cassette (ABC) transporters

P-glycoproteins (P-gp)

aberrant expression may cause multidrug resistance in cancer

often co-located w/ SLC transporters as "reverse pumps"

against the concentration gradient

plasma proteins

drug binding results in non-linear increases in free-drug concentrations in plasma

high conc drugs can saturate binding sites on proteins

competition for binding on plasma proteins

high affinity drugs displace low affinity drugs

although most drugs not in large enough quantities for displacement to be a significant factor in free concentration

ex. predominantly albumin

What? continual process of drug distribution into liquid or aqueous compartments of the body

aqueous compartments

aqueous cytoplasm of cells = chief reservoirs for water soluble drugs

other compartments act as reservoirs for drug dissolution

plasma

body fat

interstitial water

Volume of Distribution (Vd)

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D = dose
C0 = plasma concentration at time zero

comparing volume in circulation and everywhere else

blood samples allow us to estimate where drug primarily resides

High: drug has left circulation
Low: drug primarily still in circulation

does NOT take into account metabolism of drug

relevant immediately after administration

Blood Brain Barrier

Non-brain capillary: fenestrations in endothelial cell lined blood vessels

Brain capillary: tight junctions so solutes must pass through two lipid membranes

most drugs & large molecules excluded

highly lipophilic drugs may cross BBB

Drug --> Derivative --> Conjugate

Where? liver is the main site of metabolism

prepares drug for elimination by making it more water soluble

Stages:

Phase 1

Phase 2

primarily oxidation

increase water solubility

reduction & hydrolysis too

primarily mediated by cytochrome system associated w/ ER in cells

conjugation of side chains to drugs

glucuronidation, sulphation, glutathione addition, glycine or water conjugation, methylation

produces polar molecule that is readily excreted

First Pass Effect

metabolism of drugs prior to reaching circulation

absorption from small intestine direct to hepatic portal vein

Drugs most affected

ex. lidocaine

active drug removed in liver during first pass

must be injected near target site, can't be administered orally

bioavailability= drug that reaches circulation

Prodrugs

inactive drug precursors that utilize the first pass effect to produce an active drug

takes place mainly in the liver

genetic variation of p450 enzyme

primary drug metabolizing enzymes =
CYP1, CYP2, CYP3

primary causes of individual patient response variation

add a reactive residue to processed molecule

can turn inactive pro-drug into active drug

can create a reactive toxic metabolite from another drug

reactive group from Phase 1 may act as a target site for conjugation system of Phase 2

cytochrome p450 enzymes

iron bearing haem proteins

net effect of action is addition of oxygen or hydroxyl

mainly take place in liver

via

Hepatic Route

transport of drugs from plasma to bile via SLC & P-gp transporters

enterohepatic circulation can re-uptake excreted drugs

Renal Route

glomerular filtration

active tubular secretion

passive diffusion across tubular epithelium

molecules <5,000-15,000mw readily pass

plasma proteins like albumin do not pass

plasma protein-bound drug will therefore not pass

transport via carriers (OAT, OCT)

highly lipophilic drugs or those non-ionized in urine may be resorbed

pH control of drug excretion

99% of water exiting circulation via glomerular filtration is reabsorbed as fluid passes along tubule

drugs are passively reabsorbed along concentration gradient made by resorption of water

ion trapping

increased basic drug excretion in acidic urine

increases acidic drug excretion in alkaline urine

clearance - drug excretion by liver or kidneys

Plasma clearance (Cl) = volume of plasma cleared of drug per unit time (ml/min)

indicator of efficiency of drug removal from plasma

primary excretion via urine, but also feces, breath, sweat, saliva, tears, breast milk

total body clearance = sum of all the clearances by various mechanisms