Pharmacokinetics: ADME and Drug Distribution

Clinical Pharmacology, Lecture 1. This lecture addresses pharmacokinetics (PK) — what the body does to a drug — covering the four ADME processes: Absorption, Distribution, Metabolism, and Excretion.

ABSORPTION

Absorption refers to the movement of drug from the site of administration into the systemic circulation. For orally administered drugs, the key determinants are:

1. Physico-chemical properties: lipophilic, un-ionised drugs cross cell membranes more readily than hydrophilic or ionised ones. The Henderson-Hasselbalch equation predicts the degree of ionisation based on pKa and local pH. Weak acids (e.g., aspirin, pKa ~3.5) are predominantly un-ionised and absorbed in the acidic stomach; weak bases are absorbed in the alkaline small intestine. However, the large surface area of the small intestine means most oral drug absorption occurs there regardless.

1. First-pass effect (pre-systemic metabolism): orally absorbed drugs pass via the portal circulation to the liver before reaching the systemic circulation. Drugs with high hepatic extraction ratios (e.g., morphine, lignocaine, propranolol) undergo extensive first-pass metabolism, dramatically reducing oral bioavailability. This explains why oral morphine doses are higher than parenteral doses to achieve equivalent effect.

1. Bioavailability (F): the fraction of administered dose that reaches the systemic circulation unchanged. IV administration: F = 1 by definition. Sublingual and rectal routes partially bypass first-pass metabolism, increasing bioavailability for some drugs (e.g., glyceryl trinitrate is given sublingually because it has essentially zero oral bioavailability due to first-pass extraction).

DISTRIBUTION

Once in the systemic circulation, drugs distribute into body compartments. The key parameter is the Volume of Distribution (Vd):

Vd = Amount of drug in body / Plasma drug concentration

Vd is an apparent (not real) volume. A drug with Vd close to plasma volume (~3 L) is largely confined to plasma (e.g., large, protein-bound molecules like heparin). A drug with Vd close to total body water (~42 L) distributes into tissues. A Vd much larger than total body water (e.g., chloroquine Vd ~800 L/kg, amiodarone Vd ~60 L/kg) indicates extensive tissue binding; the drug is sequestered in peripheral tissues, and the plasma concentration is therefore very low relative to the total body load.

Plasma protein binding: most drugs bind to albumin (acidic drugs) or alpha-1-acid glycoprotein (basic drugs). Only free (unbound) drug is pharmacologically active. Clinically significant displacement interactions occur only for highly protein-bound drugs with a narrow therapeutic index in a limited distribution space (rare in practice for most drugs).

Blood-brain barrier (BBB): a specialised endothelium with tight junctions and P-glycoprotein efflux pumps restricts entry of hydrophilic and charged molecules. CNS-active drugs must be lipophilic and un-ionised (e.g., diazepam, morphine). P-glycoprotein can be inhibited (e.g., by verapamil) to increase CNS drug penetration.

METABOLISM

Hepatic metabolism transforms drugs into more water-soluble (polar) compounds for excretion. Two phases:

Phase I (functionalisation): introduces or uncovers a polar functional group. Predominantly via cytochrome P450 (CYP) enzymes in the smooth ER of hepatocytes. Major CYP isoforms: CYP3A4 (metabolises ~50% of drugs; induced by rifampicin, carbamazepine; inhibited by ketoconazole, grapefruit juice), CYP2D6 (codeine→morphine; inhibited by fluoxetine, paroxetine — "2D6 duds" mnemonic), CYP2C9 (warfarin, NSAIDs; induced by rifampicin), CYP2C19 (omeprazole, clopidogrel — pro-drug requires activation).

Phase II (conjugation): attaches a polar moiety (glucuronide, sulphate, acetyl, methyl, glutathione) to produce a water-soluble conjugate for renal or biliary excretion. Usually inactivates the drug, though some conjugates are pharmacologically active (morphine-6-glucuronide is more potent than morphine).

Enzyme induction: rifampicin, carbamazepine, phenytoin, St John's Wort — increase CYP expression via nuclear receptors, accelerating metabolism of co-administered drugs and reducing their plasma levels. Clinical consequence: oral contraceptive failure, reduced warfarin anticoagulation.

Enzyme inhibition: ketoconazole, erythromycin, grapefruit juice (furanocoumarin), amiodarone, fluconazole — inhibit CYP, increasing plasma levels of co-administered substrates and risk of toxicity. Grapefruit inhibits intestinal CYP3A4, most relevant for statins and ciclosporin.

EXCRETION

The kidneys are the primary route for polar/water-soluble drugs. Renal drug clearance involves glomerular filtration, active tubular secretion (e.g., OAT/OCT transporters for many drugs), and passive tubular reabsorption. Urinary acidification increases ionisation of basic drugs (trapping them in tubular urine), enhancing excretion — exploited in amphetamine and methadone toxicity.

Biliary excretion: large, conjugated drugs (>400 Da) undergo biliary excretion into the gut; intestinal bacteria may hydrolyse the conjugate, releasing the drug for reabsorption (enterohepatic recirculation), prolonging action (e.g., ethinyloestradiol).

Half-life (t1/2): the time for plasma concentration to halve. For first-order kinetics: t1/2 = 0.693 × Vd / CL. Steady-state is reached after approximately 4-5 half-lives. Loading doses are used when rapid steady-state is needed (e.g., digoxin, amiodarone).

Clearance (CL): the volume of plasma cleared of drug per unit time. Total CL = renal CL + hepatic CL + other. For renally excreted drugs, dose adjustment is needed when GFR is reduced (e.g., aminoglycosides, metformin, lithium, digoxin).