C08CA13 - Lercanidipine |
Propably not porphyrinogenic |
PNP |
Rationale
Although lercanidipine possesses a tertiary amin, a functional group that has been associated with MI-complex formation and mechanism-based inhibition of CYP enzymes in other substrates, lercanidipine has not been reported to be mechanism-based inhibitor of any CYP enzymes.
Chemical description
Dihydropyridine calcium antagonist
Therapeutic characteristics
Lercanidipine is used in the treatment of mild to moderate essential hypertension. It is administered orally.
Metabolism and pharmakokinetics
Lercanidipine is extensively metabolized by CYP3A4 (Klotz 2002, SPC).
In vitro studies with human liver microsomes have found lercanidipine to inhibit CYP3A4 and CYP2D6 (SPC). However, inhibition was found at concentrations 150-fold higher than the maximal plasma concentration after administration of doses of 20 mg. In vivo coadministration of lercanidipin and the CYP3A4 substrate simvastatin showed a 56 % and 28 % increase in the AUC of simvastatin and its active metabolite, respectively (Zhou 2013). According to the FDAs classification of inhibitors, lercanidipine may thus be described as a weak inhibitor of CYP3A4 in vivo (FDA).
On the other hand lercanidipine did not alter the metabolism of the CYP3A4 substrate midazolam or the CYP2D6 substrate metoprolol, when coadministrated in vivo (McClellan 2000).
Lercanidipine possesses a tertiary amine. Tertiary amines may undergo N-dealkylation resulting in a metabolic intermediate which has been shown in other drugs to cause mechanism-based inhibition of CYP enzymes (Riley 2007, Zhou 2007). Lercanidipine has not been reported to be a mechanism-based inhibitor of any CYP enzymes.
Lercanidinpine is not listed as a mechanism-based inhibitor or an inducer (Hisaka 2010, Isoherranen 2009, Pelkonen 2008).
IPNet drug reports
Uneventful use reported in 1 patient with acute porphyria.
References
- Scientific articles
- Zhou YT, Yu LS , et al. Pharmacokinetic drug-drug interactions between 1,4-dihydropyridine calcium channel blockers and statins: factors determining interaction strength and relevant clinical risk management. Ther Clin Risk Manag. 2014;10:17-26. #1305
- Hisaka A, Ohno Y, et al. Prediction of pharmacokinetic drug-drug interaction caused by changes in cytochrome P450 activity using in vivo information. Pharmacol Ther. 2010 Feb;125(2):230-48. #1138
- Isoherranen N, Hachad H, et al. Qualitative analysis of the role of metabolites in inhibitory drug-drug interactions: literature evaluation based on the metabolism and transport drug interaction database. Chem Res Toxicol. 2009 Feb;22(2):294-8. #1005
- Klotz U. Interaction potential of lercanidipine, a new vasoselective dihydropyridine calcium antagonist. Arzneimittelforschung. 2002;52(3):155-61. PMID 11963641. #1299
- McClellan KJ, Jarvis B. Lercanidipine: a review of its use in hypertension. Drugs. 2000 Nov;60(5):1123-40. PMID 11129125. #1300
- Pelkonen O, Turpeinen M, et al. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008 Oct;82(10):667-715. PMID 18618097. #4347
- Riley RJ, Grime K, et al. Time-dependent CYP inhibition. Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):51-66. #1303
- Zhou SF, Xue CC, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007 Dec;29(6):687-710. PMID 18043468. #4349
- Government bodies
- #1302
- Drug interaction databases
- U.S.FoodandDrugAdministration (FDA). (27.10.2014). "Drug Developement and Drug Interactions: Table of Substrates, Inhibitors and Inducers." Retrieved 14.04.2015, from #1301
- Summary of Product Characteristics
- The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). (Zanidip). #1304
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