What are the pharmacokinetic properties of amlodipine, including absorption, bioavailability, protein binding, volume of distribution, metabolism, elimination, half‑life, and dosing adjustments in hepatic or renal impairment?

Amlodipine Pharmacokinetics

Amlodipine has a unique pharmacokinetic profile among calcium channel blockers, characterized by slow absorption, high bioavailability (64-90%), extensive hepatic metabolism with minimal renal clearance, very long half-life (30-50 hours), and high protein binding (93%), making it ideal for once-daily dosing without significant dose adjustments in renal impairment. 1

Absorption

• Peak plasma concentrations occur 6-12 hours after oral administration, reflecting gradual absorption from the gastrointestinal tract 1, 2, 3
• Absolute bioavailability ranges from 64% to 90%, which is substantially higher than most other dihydropyridines (typically 10-30%) 1, 3, 4
• Food does not alter amlodipine's bioavailability 1
• The slow absorption pattern is attributable to amlodipine's chemical structure and positive ionic charge at physiological pH 5

Distribution

• Volume of distribution is large at approximately 21 L/kg, indicating extensive tissue distribution 3
• Approximately 93% of circulating drug is bound to plasma proteins (primarily albumin) in hypertensive patients 1
• The high degree of ionization contributes to distinctive distribution characteristics compared to other dihydropyridines 3, 5

Metabolism

• Amlodipine is extensively metabolized (approximately 90%) to inactive metabolites via hepatic metabolism, with no significant first-pass metabolism 1, 3
• Only 10% of the parent compound is excreted unchanged in urine, with 60% excreted as metabolites 1
• CYP3A4 is the primary metabolic pathway 1

Drug Interactions Affecting Metabolism

• Strong CYP3A4 inhibitors (itraconazole, clarithromycin) may significantly increase amlodipine plasma concentrations 1
• Diltiazem 180 mg daily increased amlodipine systemic exposure by 60% in elderly hypertensive patients 1
• Cimetidine, antacids, sildenafil, and grapefruit juice have no impact on amlodipine exposure 1
• Erythromycin does not significantly alter amlodipine pharmacokinetics 1

Elimination

• Terminal elimination half-life is 30-50 hours, which is dramatically longer than other calcium antagonists (typically 3-10 hours) 1, 3, 4, 6
• Elimination is biphasic with a prolonged terminal phase 1
• Steady-state plasma levels are reached after 7-8 days of consecutive daily dosing 1, 3
• Low clearance combined with high volume of distribution accounts for the extended half-life 2, 6

Special Populations

Renal Impairment

• Amlodipine pharmacokinetics are NOT significantly influenced by renal impairment 1, 2
• Patients with renal failure may receive the usual initial dose without adjustment 1
• This is a critical advantage over many cardiovascular drugs that require dose reduction in chronic kidney disease 7

Hepatic Impairment

• Elderly patients and those with hepatic insufficiency have decreased clearance, resulting in AUC increases of approximately 40-60% 1
• In patients with cirrhosis, elimination half-life is significantly prolonged (60 vs 34 hours) 4
• A lower initial dose is required in hepatic impairment 1
• Drugs with high hepatic extraction ratios require dose adjustments with aging due to decreased hepatic blood flow, though amlodipine has low intrinsic clearance 7

Elderly Patients

• Elimination half-life is significantly prolonged in elderly patients (48 vs 35 hours), suggesting decreased oral clearance or increased bioavailability 4
• Clearance decreases by approximately 40-60% in elderly patients 1
• Age-related decreases in hepatic blood flow and liver mass (20-30%) contribute to altered pharmacokinetics 7

Pediatric Patients

• In hypertensive patients aged 6-17 years, weight-adjusted clearance and volume of distribution are similar to values in adults 1

Clinical Implications

• The long half-life and slow absorption produce relatively small peak-to-trough fluctuations in plasma concentrations, avoiding sharp fluctuations associated with vasodilation-induced side effects (tachycardia, headache, flushing) seen with other calcium antagonists 2, 5
• Once-daily dosing maintains mean effective plasma levels throughout the 24-hour dosing interval 1, 2
• The pharmacokinetic profile results in a smoother pharmacodynamic effect with reduced incidence of early vasodilator side effects 5
• Amlodipine shows linear dose-related pharmacokinetic characteristics at steady-state 3

Protein Binding Considerations

• Despite high protein binding (93%), changes in plasma albumin levels with aging have limited clinical relevance, as effects on free plasma concentration are rapidly counterbalanced by effects on clearance 7
• In elderly patients, decreased plasma albumin could theoretically increase free drug levels of highly albumin-bound drugs, though this is not clinically significant for amlodipine dosing 7