Absorption & Distribution

Drug absorption describes the movement of a drug from its site of administration into the systemic circulation. The route of administration profoundly influences the speed and extent of absorption. Intravenous (IV) administration delivers drug directly into plasma, bypassing absorption entirely and achieving 100% bioavailability. Intramuscular (IM) and subcutaneous (SC) routes rely on diffusion through tissue into capillaries. Oral administration is most convenient but subjects drugs to first-pass metabolism: drug absorbed from the GI tract enters the portal circulation and passes through the liver before reaching systemic circulation, where hepatic enzymes can substantially reduce the amount of drug reaching the target. Bioavailability (F) quantifies this: F = (AUC_oral / AUC_IV) × (Dose_IV / Dose_oral). Transdermal administration avoids first-pass effect but is limited to lipophilic, low-molecular-weight drugs.

GI absorption is governed by the pH-partition hypothesis. Drugs cross membranes in their unionised, lipophilic form. Weak acids (low pKa) are predominantly unionised in the acidic stomach, favouring absorption there; weak bases are better absorbed in the more alkaline small intestine. Lipophilicity (log P) strongly predicts membrane permeability. P-glycoprotein (P-gp), an efflux transporter expressed in gut epithelium, actively pumps drugs back into the intestinal lumen, limiting absorption of many substrates including digoxin and cyclosporine.

Volume of distribution (Vd) describes the apparent space in which drug distributes. Vd = Dose / C0, where C0 is the initial plasma concentration after IV bolus. A low Vd (~5 L) indicates drug confined to plasma — typical of large proteins like heparin. A high Vd (hundreds to thousands of L) indicates extensive tissue sequestration, as seen with chloroquine (Vd >200 L/kg) and amiodarone.

Plasma protein binding is a critical determinant of distribution and pharmacological activity. Only free (unbound) drug crosses membranes, exerts pharmacological effects, and is subject to elimination. Albumin is the principal binding protein for acidic drugs: warfarin (99% bound), phenytoin (90% bound). Alpha-1-acid glycoprotein (AAG) binds basic drugs such as lidocaine and propranolol. Displacement interactions (e.g., sulfonamides displacing warfarin from albumin) can transiently increase free drug levels, raising toxicity risk.

Specialised barriers further modulate distribution. The blood-brain barrier (BBB) comprises tight junctions between brain capillary endothelial cells plus P-gp efflux, restricting CNS entry to lipophilic, non-P-gp-substrate drugs. The placental barrier is less restrictive; lipophilic drugs such as thiopental and volatile anaesthetics cross readily, an important consideration in obstetric pharmacology. Clinical relevance: warfarin's high PPB (99%) means that a small displacement increases free warfarin markedly, explaining many drug interactions; chloroquine's vast Vd makes haemodialysis ineffective in overdose.