Received for publication July 14, 2005.
Revised February 21, 2006.
Accepted for publication February 21, 2006.

Human Cytochrome P450 Induction and Inhibition Potential of Clevidipine and Its Metabolte H152/81

Abstract

Clevidipine is a short-acting dihydropyridine calcium channel antagonist under development for treatment of peri-operative hypertension. Patients treated with clevidipine are likely to be co-medicated. Therefore the potential for clevidipine and its major metabolite H152/81 to elicit drug interactions by induction or inhibition of cytochrome P450 was investigated. Induction of CYP1A2, CYP2C9 and CYP3A4 was examined in primary human hepatocytes treated with clevidipine at 1, 10 and 100 µM. Clevidipine was found to be an inducer of CYP3A4, but not of CYP1A2 or CYP2C9, at the 10 µM and 100 µM concentrations of clevidipine tested. Induction response for CYP3A4 to 100 µM clevidipine was approximately 20% of that of the positive control inducer rifampicin. The response of H152/81 was similar. Using cDNA-expressed enzymes, clevidipine inhibited CYP2C9, CYP2C19 and CYP3A4 activities with IC₅₀ values below 10 µM, whereas CYP1A2, CYP2D6 and CYP2E1 activities were not substantially inhibited (IC50 values > 70 µM). The Ki values for CYP2C9 and CYP2C19 were 1.7 and 3.3 µM, respectively and that for CYP3A4 was 8.3 and 2.9 µM using two substrates, testosterone and midazolam, respectively. These values are at least 10 times higher than the highest clevidipine concentration typically seen in the clinic. Little or no inhibition by H152/81 was found for the enzyme activities mentioned above (IC₅₀ values 69 µM). The present study demonstrates that it is highly unlikely for clevidipine or its major metabolite to cause cytochrome P450 related drug interactions when used in the dose range required to manage hypertension in man.

Key words: CYP induction, CYP inhibition, cytochrome P450, drug interactions, enzyme kinetics, hepatocytes, human CYP enzymes, in vitro-in vivo prediction, microsomes

This article has been cited by other articles:

				J. H. Levy, M. Y. Mancao, R. Gitter, D. J. Kereiakes, A. M. Grigore, S. Aronson, and M. F. Newman Clevidipine Effectively and Rapidly Controls Blood Pressure Preoperatively in Cardiac Surgery Patients: The Results of the Randomized, Placebo-Controlled Efficacy Study of Clevidipine Assessing Its Preoperative Antihypertensive Effect in Cardiac Surgery-1 Anesth. Analg., October 1, 2007; 105(4): 918 - 925. [Abstract] [Full Text] [PDF]