Abstract
The ability of antipsychotic drugs to inhibit the catalytic activity of five cytochrome P-450 (CYP) isoforms was compared using in vitro human liver microsomal preparations to evaluate the relative potential of these drugs to inhibit drug metabolism. The apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data. All antipsychotic drugs tested competitively inhibited dextromethorphanO-demethylation, a selective marker for CYP2D6, in a concentration-dependent manner. Thioridazine and perphenazine were the most potent, with IC50 values (2.7 and 1.5 μM) that were comparable to that of quinidine (0.52 μM). The estimatedKi values for CYP2D6-catalyzing dextrorphan formation were ranked in the following order: perphenazine (0.8 μM), thioridazine (1.4 μM), chlorpromazine (6.4 μM), haloperidol (7.2 μM), fluphenazine (9.4 μM), risperidone (21.9 μM), clozapine (39.0 μM), and cis-thiothixene (65.0 μM). No remarkable inhibition of other CYP isoforms was observed except for moderate inhibition of CYP1A2-catalyzed phenacetinO-deethylation by fluphenazine (Ki = 40.2 μM) and perphenazine (Ki = 65.1). The estimatedKi values for the inhibition of CYP2C9, 2C19, and 3A were >300 μM in almost all antipsychotics tested. These results suggest that antipsychotic drugs exhibit a striking selectivity for CYP2D6 compared with other CYP isoforms. This may reflect a remarkable commonality of structure between the therapeutic targets for these drugs, the transporters, and metabolic enzymes that distribute and eliminate them. Clinically, coadministration of these medicines with drugs that are primarily metabolized by CYP2D6 may result in significant drug interactions.
Footnotes
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Send reprint requests to: Dr. David A. Flockhart, M.D., Ph.D., Assistant Professor of Medicine and Pharmacology, Division of Clinical Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20007. E-mail:FLOCKHAD{at}medlib.georgetown.edu
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↵1 Presented in part at the 99th meeting of the American Society for Clinical Pharmacology and Therapeutics in New Orleans, LA, March 1998.
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This study was supported in part by a Shannon Director’s award (D.A.F.) R55-GM56898, and by National Institute of General Medical Sciences (Bethesda, MD) Grants R01-GM56898–01 and T32–9M08386. J.-G.S. was supported by a Merck Sharp & Dohme International Fellowship Award in Clinical Pharmacology.
- Abbreviations used are::
- CYP
- cytochrome P-450
- G-6-P
- glucose 6-phosphate
- G-6-PDH
- glucose 6-phosphate dehydrogenase
- HL
- human liver microsomes
- MHL
- mixed human liver microsomes
- Received January 21, 1999.
- Accepted May 7, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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