Time-Dependent Inhibitory Effects of (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-Dihydroxy-12-(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylvinyl-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(2-oxopropyl)-11,28-dioxa-4-azatricyclo[22.3.1.04.9]octacos-18-ene-2,3,10,16-tetrone (FK1706), a Novel Nonimmunosuppressive Immunophilin Ligand, on CYP3A4/5 Activity in Humans in Vivo and in Vitro

Autor: Tsuyoshi Minematsu, Katsuyuki Hori, Takashi Usui, Jiuhong Zha, Selina Moy, Jennifer Lee, Koji Ishibashi, Hidetaka Kamimura, Donna Kowalski
Rok vydání: 2009
Předmět:
Zdroj: Drug Metabolism and Disposition. 38:249-259
ISSN: 1521-009X
0090-9556
DOI: 10.1124/dmd.109.029280
Popis: We investigated the inhibitory effects of FK1706, a novel non-immunosuppressive immunophilin ligand, on CYP3A4/5 in in vitro and in vivo settings. First, the inhibitory effects of FK1706 (preincubation dependency, inactivation rate estimation, and reversibility) were tested using human liver microsomes. Second, the effect of repeated oral dose of FK1706 (60 mg q.d. for 14 days) on the pharmacokinetics of midazolam (single oral 2 mg dose) was tested in healthy volunteers. Finally, pharmacokinetic modeling and simulation were performed. In vitro experiments showed that FK1706 inhibited CYP3A4/5 in time-dependent and irreversible manner. In vitro maximum inactivation rate constant (k inact ) and concentration of inhibitor that gave half-maximal k inact (K I ) were estimated to be 10.1 h -1 and 2,050 ng/mL, respectively. In the clinical study, FK1706 produced a two-fold increase in area under the time-concentration curve (AUC) of midazolam. A pharmacokinetic model developed for this study which described the time course of concentrations of both FK1706 and midazolam and incorporated CYP3A4/5 inactivation in the liver and intestine successfully predicted the change in the pharmacokinetics of midazolam using in vitro k inact and K I values (1.66- to 2.81-fold increase in AUC predicted), and estimated the in vivo inactivation rate to be 0.00404 to 0.0318 h -1 ·mL/ng. In conclusion, FK1706 weakly or moderately inhibited the activity of CYP3A4/5 in vitro and vivo at the tested dose. The model developed here would be helpful in predicting drug-drug interactions and in the design of dose regimens which avoided drug-drug interactions.
Databáze: OpenAIRE
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