title: In vitro-in vivo extrapolations to evaluate the effect of concomitant drugs on tacrolimus (FK506) exposure.
abstract: The effect of concomitant drugs having a cytochrome P450 (CYP) 3A inhibitory potency on tacrolimus exposure was predicted from in vitro metabolism results. In this study, the IC₅₀ values of concomitant drugs on the formation of M-I, the major metabolite of tacrolimus, were determined, and the effect on oral exposure (AUCp.o.) of tacrolimus was assessed from static models. When an absorbed fraction (Fa ) of 0.97, intestinal wall availability (Fg) of 0.27 and fraction metabolized by CYP3A (fm(CYP3A)) of 0.8 were used, the least bias was observed for the prediction of the AUCp.o. of tacrolimus. The relationship of the IC₅₀ values of 11 inhibitors between tacrolimus and typical CYP3A substrates (midazolam and testosterone) was also analysed. A strong correlation was found between the IC₅₀ values of tacrolimus and typical CYP3A substrates (r(2)  ≥ 0.85). The predictability of the effect of inhibitors on tacrolimus AUCp.o. was investigated based on the same static models with the use of published IC₅₀ values for midazolam and testosterone. The bias for the prediction of tacrolimus AUCp.o. was minimal with the use of IC₅₀ values determined using tacrolimus itself as a substrate. These results suggest that tacrolimus itself is still the best choice for predicting the AUCp.o. of tacrolimus, although our findings suggest that midazolam or testosterone may be used instead of tacrolimus to estimate roughly (predicted AUCp.o. within an approximately 2-fold range of observed values) the effect of CYP3A inhibitors on the tacrolimus AUCp.o.
authors.affiliation: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., Yodogawa-ku, Osaka, 532-8514, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Oda
authors.affiliation: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., Yodogawa-ku, Osaka, 532-8514, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Yamano
authors.affiliation: Analysis and Pharmacokinetics Research Laboratories, Astellas Pharma Inc., Yodogawa-ku, Osaka, 532-8514, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Otsuka
mesh_terms: D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000378:metabolism; D008874:Midazolam / Q000494:pharmacology; D008954:Models, Biological; D016559:Tacrolimus / Q000494:pharmacology*; D013739:Testosterone / Q000494:pharmacology
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D007166:Immunosuppressive Agents; D013739:Testosterone; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam; D016559:Tacrolimus
keywords: FK506; drug-drug interaction; microsomes; prediction; tacrolimus