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

Abstract

ABSTRACT:Clevidipine is a short-acting dihydropyridine calcium channel antagonist under development for treatment of perioperative hypertension. Patients treated with clevidipine are likely to be comedicated. 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 M. Clevidipine was found to be an inducer of CYP3A4, but not of CYP1A2 or CYP2C9, at the 10 M and 100 M concentrations of clevidipine tested. Induction response for CYP3A4 to 100 M 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 IC 50 values below 10 M, whereas CYP1A2, CYP2D6, and CYP2E1 activities were not substantially inhibited (IC 50 values >70 M). The K i values for CYP2C9 and CYP2C19 were 1.7 and 3.3 M, respectively, and those for CYP3A4 were 8.3 and 2.9 M, 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 (IC 50 values > 69 M). 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 humans.Clevidipine (CLE), butyroxymethyl methyl 4-(2Ј, 3Ј-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate ( Fig. 1), is in phase III clinical trials as a rapid acting calcium channel antagonist for intravenous control of blood pressure (Nordlander et al., 2004). Clevidipine is rapidly hydrolyzed and inactivated by esterases in blood and extravascular tissues to its primary metabolite H152/81 (Ericsson et al., 1999(Ericsson et al., , 2000. CLE may have advantages over other antihypertensives. For example, CLE effectively controlled blood pressure in hypertensive patients after undergoing elective coronary bypass grafting, and hemodynamic changes were less pronounced with CLE, compared with sodium nitroprusside (Powroznyk et al., 2003). CLE successfully decreased systemic vascular resistance and mean arterial pressure without changing heart rate, cardiac index, or cardiac filling pressures (Bailey et al., 2002).Clevidipine is a member of the dihydropyridine class of compounds, which have been shown to be inducers and/or inhibitors of cytochromes P450. For example, nifedipine, nicardipine, and isradipine are potent inducers for CYP3A4, CYP2B, and CYP2C in human hepatocyte cultures (Drocourt et al., 2001), and nifedipine induces CYP2C in coronary artery segment endothelial cells (Fisslthaler et al., 2000). In addition, nicardipine, benidipine, manifipine, and barnidipine are potent inhibit...

Regulation of cytochrome P450 2C9 expression in primary cultures of human hepatocytes

“…Additional reports demonstrated that rifampin, dexamethasone and phenobarbital increased the amount of immunoreactive CYP2C proteins [15,16]. Clevidipine, a dihydropyridine calcium channel antagonist was found to be a moderate inducer of CYP3A4, but not of CYP2C9 in primary human hepatocyte cultures at 10 and 100 μM concentrations [17]. However, it is possible that the lack of CYP2C9 induction observed in this study was due to concomitant inhibition, as clevidipine is a potent CYP2C9 inhibitor with a K i of 1.7 μM.…”

Evaluation of Multiple in Vitro Systems for Assessment of CYP3A4 Induction in Drug Discovery: Human Hepatocytes, Pregnane X Receptor Reporter Gene, and Fa2N-4 and HepaRG Cells

“…The CYP3A4 induction assay was performed essentially as described by Zhang et al (2006). In brief, the induction was determined by measuring the 6␤-hydroxytestosterone metabolite formation from model substrate testosterone in situ and measuring mRNA expression using TaqMan real-time RT-PCR as described below.…”

Intravenous clevidipine for management of hypertension

“…19 Approximately 99.5% of clevidipine in plasma is bound to proteins, and this binding capacity is not concentrationdependent. 18,20,21 Clevidipine is a high clearance drug, whereby the kidney is responsible for the elimination of at least 60% of the drug and the remainder is eliminated in feces.…”