Clearance: Hepatic and Renal Mechanisms

Clearance (CL) is the volume of plasma completely cleared of drug per unit time, expressed in mL/min or L/h. It is the most important pharmacokinetic parameter governing steady-state drug concentrations. The fundamental relationship is: CL = ke × Vd, where ke is the elimination rate constant. Alternatively, at steady state: CL = F × Dose / (CSS × τ), where F is bioavailability, CSS is the average steady-state concentration, and τ is the dosing interval. Total body clearance is the sum of all individual organ clearances: CLtotal = CLhepatic + CLrenal + CLother.

Hepatic clearance depends on three factors: hepatic blood flow (Q), the unbound fraction in blood (fu), and intrinsic hepatic clearance (CLint). The relationship is described by the well-stirred model: CLhepatic = Q × fu × CLint / (Q + fu × CLint). This equation yields two important drug classification extremes. High extraction ratio drugs (ER > 0.7) have CLhepatic ≈ Q — their clearance is blood flow–limited. Examples include lignocaine, propranolol, morphine, verapamil, and GTN. For these drugs, hepatic blood flow is the rate-limiting factor; changes in enzyme activity have little effect, but changes in cardiac output (heart failure, haemorrhage) or drugs that alter hepatic blood flow dramatically affect clearance. The first-pass effect is pronounced for high-extraction drugs administered orally — oral bioavailability can be as low as 10–30% because the drug is extensively cleared on first passage through the gut wall and liver.

Low extraction ratio drugs (ER < 0.3) have CLhepatic ≈ fu × CLint — their clearance is capacity-limited and sensitive to both protein binding changes and enzyme induction or inhibition. Examples include warfarin, phenytoin, diazepam, and theophylline. Enzyme inducers (rifampicin, phenobarbitone, carbamazepine) substantially increase CLint and therefore clearance for these drugs, reducing plasma concentrations and therapeutic effect. Enzyme inhibitors (fluconazole, erythromycin, amiodarone) reduce CLint and increase drug concentrations, raising toxicity risk.

Renal clearance encompasses three processes: glomerular filtration, tubular secretion, and tubular reabsorption. CLrenal = (GFR × fu) + CLsecretion − CLreabsorption. Glomerular filtration rate (GFR) is the starting point — approximately 125 mL/min in healthy adults, declining with age and renal disease. Only unbound drug is filtered. Active tubular secretion via organic anion transporters (OAT1, OAT3) and organic cation transporters (OCT2) in the proximal tubule can exceed GFR and is saturable. Classic examples include penicillin (secreted by OAT), metformin (secreted by OCT2), and probenecid (which competitively inhibits penicillin secretion — historically used to prolong penicillin action). Tubular reabsorption is passive and pH-dependent — alkalinisation of urine traps ionised aspirin in the tubule and increases its renal clearance, the basis of urinary alkalinisation in aspirin overdose.

In New Zealand clinical practice, eGFR (estimated using the CKD-EPI equation) guides dose adjustment for renally cleared drugs. Pharmac Special Authority criteria often specify dose reductions at eGFR thresholds (e.g., dabigatran contraindicated below eGFR 30 mL/min/1.73m², metformin dose reduction below 45 mL/min/1.73m²). Medsafe datasheets provide specific guidance for renal impairment dosing.