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Effect of telaprevir on the metabolism and hepatic uptake of tacrolimus (FK506)
Author(s) -
Oda Kazuo,
Yamano Katsuhiro
Publication year - 2014
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.1913
Subject(s) - telaprevir , tacrolimus , cyp3a4 , pharmacology , pharmacokinetics , microsome , metabolite , chemistry , metabolism , cytochrome p450 , in vitro , medicine , biology , biochemistry , transplantation , ribavirin , genotype , gene
Telaprevir, a chronic hepatitis C virus (HCV) protease inhibitor, is known to be a cytochrome P450 (CYP) 3A4/5 substrate and inhibitor. In the present study, the in vitro inhibitory effect of telaprevir on the metabolism of tacrolimus in human liver microsomes was investigated using 13‐ O ‐demethyltacrolimus (M‐I) as a monitor metabolite. Telaprevir inhibited M‐I formation in a time‐dependent fashion with rate of enzyme inactivation ( k inact ) and concentration to reach 50% of k inact ( K I ) values of 0.113 min ‐1 and 0.511 µ m , respectively. Using the inhibition parameters generated, in vitro–in vivo extrapolations were performed to evaluate the clinical relevance of the effect of telaprevir on the area under the curve versus time ( AUC ) of tacrolimus. When 750 mg of telaprevir was administered orally, the intestinal wall availability ( F g ) of tacrolimus was estimated to be increased 3.7‐ to 7.0‐fold. The hepatic intrinsic clearance ( CL int ) of tacrolimus was also estimated to be decreased 4.4‐ to 19‐fold. These results suggest that the increased AUC of tacrolimus in the presence of telaprevir was caused by intestinal and hepatic metabolism inhibition. In addition, the inhibitory effect of telaprevir on the hepatic uptake of tacrolimus was also examined using human cryopreserved hepatocytes. However, no significant inhibitory effect was noted, suggesting that the effect of telaprevir on hepatic transporters did not contribute to the increase in tacrolimus exposure. Copyright © 2014 John Wiley & Sons, Ltd.