Abstract
We compared the intestinal metabolism of the structurally related 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors lovastatin and pravastatin in vitro. Human small intestinal microsomes metabolized lovastatin to its major metabolites 6′β-hydroxy (apparentKm = 11.2 ± 3.3 μM) and 6′-exomethylene (apparent Km = 22.7 ± 9.0 μM) lovastatin. The apparentKm values were similar for lovastatin metabolism by human liver microsomes. 6′β-Hydroxylovastatin formation by pig small intestinal microsomes was inhibited with the following inhibition Ki values: cyclosporine, 3.3 ± 1.2 μM; ketoconazole, 0.4 ± 0.1 μM; and troleandomycin, 0.8 ± 0.9 μM. Ki values for 6′-exomethylene lovastatin were similar. Incubation of pravastatin with human small intestinal microsomes resulted in the generation of 3′α,5′β,6′β-trihydroxypravastatin (apparentKm = 4560 ± 1410 μM) and hydroxypravastatin (apparent Km = 5290 ± 1740 μM). In addition, as in the liver, pravastatin was metabolized in the small intestine by sulfation and subsequent degradation to its main metabolite 3′α-iso-pravastatin. It was concluded that lovastatin is metabolized by cytochrome P-450 3A enzymes in the small intestine. Compared with lovastatin, the cytochrome P-450-dependent intestinal intrinsic clearance of pravastatin was >5000-fold lower and cannot be expected to significantly affect its oral bioavailability or to be a significant site of drug interactions.
Footnotes
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Send reprint requests to: Dr. Uwe Christians, Department of Biopharmaceutical Sciences, University of California, 533 Parnassus Ave., Room U-66, San Francisco, CA 94143-0446. E-mail:uwec{at}itsa.ucsf.edu
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↵1 This study was supported by Deutsche Forschungsgemeinschaft Grants SFB265/A7, SFB280/A8, and Ch95/6-2 and National Institutes of Health Grant GM26691.
- Abbreviations:
- HMG-CoA
- 3-hydroxy-3-methylglutaryl-coenzyme A
- CYP
- cytochrome P-450
- MS
- mass spectrometry
- m/z
- mass/charge
- PAPS
- adenosine 3′-phosphate 5′-phosphosulfate
- Received June 8, 1998.
- Accepted May 3, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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