RT Journal Article
SR Electronic
T1 Inhibition and Stimulation of Intestinal and Hepatic CYP3A Activity: Studies in Humanized CYP3A4 Transgenic Mice Using Triazolam
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2305
OP 2313
DO 10.1124/dmd.109.029397
VO 37
IS 12
A1 Robert A. B. van Waterschoot
A1 Rogier W. Rooswinkel
A1 Rolf W. Sparidans
A1 Antonius E. van Herwaarden
A1 Jos H. Beijnen
A1 Alfred H. Schinkel
YR 2009
UL http://dmd.aspetjournals.org/content/37/12/2305.abstract
AB CYP3A4 is an important determinant of drug-drug interactions. In this study, we evaluated whether cytochrome P450 3A knockout mice [Cyp3a(−/−)] and CYP3A4 transgenic (CYP3A4-Tg) mice can be used to study drug-drug interactions in the liver and intestine. Triazolam was used as a probe drug because it is a highly specific CYP3A substrate and not a P-glycoprotein substrate. Triazolam metabolism was profoundly reduced in Cyp3a(−/−) mice both in vitro and in vivo. In vitro studies revealed clear species differences in humans and mice, but triazolam metabolism in microsomes derived from CYP3A4-Tg “humanized” mice closely resembled that in human microsomes. It is interesting to note that studies with tissue-specific CYP3A4-Tg mice revealed that intestinal CYP3A4 has a major impact on oral triazolam exposure, whereas the effect of hepatic CYP3A4 was limited. To mimic a drug-drug interaction, we coadministered triazolam with the prototypical CYP3A inhibitor ketoconazole, which increased triazolam exposure in all the CYP3A-proficient mouse strains but not in Cyp3a(−/−) mice. We further found that the anticancer drug gefitinib is a potent stimulator of 1′-OH triazolam formation in vitro. It is noteworthy that we could also show in vivo stimulation of triazolam metabolism by gefitinib, resulting in a lower oral triazolam exposure. To our knowledge, this is the first in vivo example of direct stimulation of CYP3A4 activity after oral drug administration. Overall, this study illustrates how Cyp3a(−/−) and CYP3A4-Tg mice can be used to study drug-drug interactions. The data clarify that for drugs that are not P-glycoprotein substrates, intestinal metabolism also can be more important than hepatic metabolism after oral administration.Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics