RT Journal Article
SR Electronic
T1 HUMAN CYTOCHROME P450 INDUCTION AND INHIBITION POTENTIAL OF CLEVIDIPINE AND ITS PRIMARY METABOLITE H152/81
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 734
OP 737
DO 10.1124/dmd.105.006569
VO 34
IS 5
A1 J. George Zhang
A1 Shangara S. Dehal
A1 Thuy Ho
A1 Jennifer Johnson
A1 Catherine Chandler
A1 Andrew P. Blanchard
A1 Robert J. Clark, Jr.
A1 Charles L. Crespi
A1 David M. Stresser
A1 James Wong
YR 2006
UL http://dmd.aspetjournals.org/content/34/5/734.abstract
AB 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 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 those for CYP3A4 were 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 humans. The American Society for Pharmacology and Experimental Therapeutics