Abstract
To select high bioavailability compounds, it is necessary to predict the first-pass metabolism in the intestine. However, in vitro-in vivo predictions of the intestinal metabolism have proven both challenging and less definitive. The purpose of this study was to investigate prediction of intestinal first-pass metabolism in humans using cynomolgus monkeys. First, we investigated intrinsic metabolic activities in intestinal microsomes of monkeys (MIM) and humans (HIM) (CLint, MIM and CLint, HIM, respectively) of 18 CYP3A substrates. The CLint, MIM values were found to be relatively high and showed excellent correlation with the CLint, HIM values. Subsequently, we determined the plasma concentrations of 9 CYP3A substrates (buspirone, carbamazepine, diazepam, felodipine, midazolam, nicardipine, nifedipine, saquinavir, and verapamil) in monkeys after an oral dose of 2 mg/kg with or without an oral dose of 5 mg/kg ketoconazole and calculated AUC(+vehicle)/AUC(+ketoconazole), defined as Fg, monkey(observed); we confirmed that the dose of ketoconazole inhibited only intestinal CYP3A metabolism by preliminary in vitro and in vivo experiments using ketoconazole. The Fg, monkey(observed) was lower than the Fg, human(observed) for most compounds, but moderate correlation was observed. Furthermore, using these data, we established a new methodology to estimate Fg, human(predicted) more precisely on the basis of the assumption that intestinal physiological conditions other than intrinsic metabolic activity would be the same between monkeys and humans. In conclusion, the in vivo model using cynomolgus monkeys in this study is useful for prediction of intestinal first-pass metabolism by CYP3A in humans because it was able to predict Fg, human of all nine compounds investigated.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.034561.
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ABBREVIATIONS:
- P450
- cytochrome P450
- MIM
- monkey intestinal microsomes
- MLM
- monkey liver microsomes
- HIM
- human intestinal microsomes
- LC
- high-performance liquid chromatography
- MS/MS
- tandem mass spectrometry
- AUC
- area under the plasma concentration-time curve
- GFJ
- grapefruit juice.
- Received May 17, 2010.
- Accepted August 11, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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