Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation.
Article Details
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Zhu Y, Wang F, Li Q, Zhu M, Du A, Tang W, Chen W
Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation.
Drug Metab Dispos. 2014 Feb;42(2):245-9. doi: 10.1124/dmd.113.055400. Epub 2013 Dec 3.
- PubMed ID
- 24301608 [ View in PubMed]
- Abstract
Amlodipine is a commonly prescribed calcium channel blocker for the treatment of hypertension and ischemic heart disease. The drug is slowly cleared in humans primarily via dehydrogenation of its dihydropyridine moiety to a pyridine derivative (M9). Results from clinical drug-drug interaction studies suggest that CYP3A4/5 mediate metabolism of amlodipine. However, attempts to identify a role of CYP3A5 in amlodipine metabolism in humans based on its pharmacokinetic differences between CYP3A5 expressers and nonexpressers failed. Objectives of this study were to determine the metabolite profile of amlodipine (a racemic mixture and S-isomer) in human liver microsomes (HLM), and to identify the cytochrome P450 (P450) enzyme(s) involved in the M9 formation. Liquid chromatography/mass spectrometry analysis showed that amlodipine was mainly converted to M9 in HLM incubation. M9 underwent further O-demethylation, O-dealkylation, and oxidative deamination to various pyridine derivatives. This observation is consistent with amlodipine metabolism in humans. Incubations of amlodipine with HLM in the presence of selective P450 inhibitors showed that both ketoconazole (an inhibitor of CYP3A4/5) and CYP3cide (an inhibitor of CYP3A4) completely blocked the M9 formation, whereas chemical inhibitors of other P450 enzymes had little effect. Furthermore, metabolism of amlodipine in expressed human P450 enzymes showed that only CYP3A4 had significant activity in amlodipine dehydrogenation. Metabolite profiles and P450 reaction phenotyping data of a racemic mixture and S-isomer of amlodipine were very similar. The results from this study suggest that CYP3A4, rather than CYP3A5, plays a key role in metabolic clearance of amlodipine in humans.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Amlodipine Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails Amlodipine Cytochrome P450 3A5 Protein Humans UnknownSubstrateInhibitorDetails Levamlodipine Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Reactions
Reaction Details - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAmlodipineAmiodarone The metabolism of Amlodipine can be decreased when combined with Amiodarone. AmlodipineMethimazole The metabolism of Amlodipine can be decreased when combined with Methimazole. AmlodipineMidostaurin The metabolism of Amlodipine can be decreased when combined with Midostaurin. AmlodipineRitonavir The metabolism of Amlodipine can be decreased when combined with Ritonavir. AmlodipineVoriconazole The metabolism of Amlodipine can be decreased when combined with Voriconazole.
