Active Metabolites of Amlodipine
Amlodipine is primarily metabolized to an inactive pyridine derivative (M9) through dehydrogenation of its dihydropyridine moiety, with no clinically significant active metabolites identified. 1
Metabolism Pathway
Amlodipine undergoes extensive hepatic metabolism through the following processes:
- Primary metabolic pathway: Dehydrogenation of the dihydropyridine moiety to form a pyridine derivative (M9) 1
- Secondary metabolism: M9 undergoes further:
- O-demethylation
- O-dealkylation
- Oxidative deamination to various pyridine derivatives 1
Enzymes Involved
- CYP3A4 is the primary enzyme responsible for amlodipine metabolism, not CYP3A5 as previously thought 1
- Studies using selective P450 inhibitors demonstrated that:
- Ketoconazole (CYP3A4/5 inhibitor) completely blocked M9 formation
- CYP3cide (specific CYP3A4 inhibitor) also completely blocked M9 formation
- Inhibitors of other P450 enzymes had minimal effect 1
Pharmacokinetic Properties
Amlodipine has distinctive pharmacokinetic characteristics:
- Slow absorption: Peak plasma concentrations occur 6-8 hours after oral administration 2
- High bioavailability: 60-65% reaches systemic circulation 2
- Extensive protein binding: 98% bound to plasma proteins 2
- Large volume of distribution: 21 L/kg 2
- Long half-life: 36-45 hours, allowing for once-daily dosing 3, 2
- No significant presystemic or first-pass metabolism 2
Clinical Implications
The lack of active metabolites contributes to amlodipine's favorable clinical profile:
- Predictable dose-response relationship: Linear pharmacokinetics with minimal fluctuations in plasma concentrations at steady state 2
- Minimal drug interactions: No clinically important drug interactions have been observed 3
- Once-daily dosing: The long half-life allows for effective 24-hour blood pressure control with once-daily administration 3, 4
Special Populations
Certain factors may influence amlodipine's pharmacokinetic profile:
- Advanced age
- Severe hepatic impairment
- Severe renal impairment
These conditions can lead to higher plasma concentrations and longer half-lives, potentially requiring dose adjustments 2.
Comparison to Other Calcium Channel Blockers
Unlike some other calcium channel blockers that may have active metabolites, amlodipine's metabolites do not contribute to its clinical effects:
- Amlodipine is more potent and longer-acting compared to newer calcium channel blockers 4
- It has high selectivity for vascular smooth muscle with minimal effect on myocardial contractility or cardiac conduction 3
- Unlike diltiazem or verapamil (which are moderate CYP3A4 inhibitors), amlodipine is primarily a CYP3A4 substrate 5
Monitoring Considerations
When monitoring patients on amlodipine therapy:
- Be aware that the full therapeutic effect may take several days to develop due to its long half-life
- Peripheral edema is the most common adverse effect 3
- No monitoring of metabolites is necessary for clinical management