Abstract
In an in vitro study, the cytochrome P-450 3A (CYP3A)-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-Co A reductase inhibitors lovastatin and pravastatin were compared. Lovastatin was metabolized by human liver microsomes to two major metabolites: 6′β-hydroxy [Michaelis-Menten constant (Km): 7.8 ± 2.7 μM] and 6′-exomethylene lovastatin (Km,10.3 ± 2.6 μM). 6′β-Hydroxylovastatin formation in the liver was inhibited by the specific CYP3A inhibitors cyclosporine (Ki, 7.6 ± 2.3 μM), ketoconazole (Ki, 0.25 ± 0.2 μM), and troleandomycin (Ki, 26.6 ± 18.5 μM). Incubation of pravastatin with human liver microsomes resulted in the generation of 3′α,5′β,6′β-trihydroxy pravastatin (Km, 4,887 ± 2,185 μM) and hydroxy pravastatin (Km, 20,987 ± 9,389 μM). The formation rates of 3′α,5′β,6′β-trihydroxy pravastatin by reconstituted CYP3A enzymes were (1,000 μM pravastatin) 1.9 ± 0.6 pmol·min−1·pmol CYP3A4 and 0.06 ± 0.04 pmol·min−1·pmol CYP3A5, and the formation rates of hydroxy pravastatin were 0.12 ± 0.02 pmol·min−1·pmol CYP3A4 and 0.02 ± 0.004 pmol·min−1·pmol CYP3A5. The specific CYP3A inhibitors cyclosporine, ketoconazole, and troleandomycin significantly inhibited hydroxy pravastatin formation by human liver microsomes, but only ketoconazole inhibited 3′α,5′β,6′β-trihydroxy pravastatin formation, suggesting that other CYP enzymes are involved in its formation. It is concluded that, compared with lovastatin [CLint formation 6′β-hydroxylovastatin (μl·min−1·mg−1): 199 ± 248, 6′-exomethylene lovastatin: 138 ± 104)], CYP3A-dependent metabolism of pravastatin [CLint formation 3′α,5′β,6′β-trihydroxy pravastatin (μl·min−1·mg−1): 0.03 ± 0.03 and hydroxy pravastatin: 0.02 ± 0.02] is a minor elimination pathway. In contrast to lovastatin, drug interactions with pravastatin CYP3A-catalyzed metabolism cannot be expected to have a clinically significant effect on its pharmacokinetics.
Footnotes
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Send reprint requests to: Uwe Christians, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California at San Francisco, 513 Parnassus Avenue, Room S-834, San Francisco, CA 94143-0446. E-mail: uwec{at}itsa.ucsf.edu
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This study was supported by Deutsche Forschungsgemeinschaft Grants SFB265/A7, SFB280/A8, and Ch95/6–1 and National Institutes of Health Grant GM26691.
- Abbreviations used are::
- CYP
- cytochrome P-450
- HLF
- human liver (female)
- HLM
- human liver (male)
- HMG
- 3-hydroxy-3-methylglutaryl
- HPLC
- high-performance liquid chromatography
- MS
- mass spectrometry
- NADPH
- reduced nicotinamide adenine dinucleotide phosphate
- Received April 8, 1998.
- Accepted July 30, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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