Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81.
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 microM. Clevidipine was found to be an inducer of CYP3A4, but not of CYP1A2 or CYP2C9, at the 10 microM and 100 microM concentrations of clevidipine tested. Induction response for CYP3A4 to 100 microM 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 microM, whereas CYP1A2, CYP2D6, and CYP2E1 activities were not substantially inhibited (IC(50) values >70 microM). The K(i) values for CYP2C9 and CYP2C19 were 1.7 and 3.3 microM, respectively, and those for CYP3A4 were 8.3 and 2.9 microM, 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 >or= 69 microM). 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.
Zhang
J George
JG
BD Biosciences Discovery Labware, Woburn, Massachusetts, USA.
Dehal
Shangara S
SS
Ho
Thuy
T
Johnson
Jennifer
J
Chandler
Catherine
C
Blanchard
Andrew P
AP
Clark
Robert J
RJ
Crespi
Charles L
CL
Stresser
David M
DM
Wong
James
J
D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004095:Dihydropyridines / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D004095:Dihydropyridines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011725:Pyridines; C511533:monomethyl 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-2,5-dicarboxylate; C118563:clevidipine; D003577:Cytochrome P-450 Enzyme System