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Research ArticleArticle

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

Tsuyoshi Minematsu, Jennifer Lee, Jiuhong Zha, Selina Moy, Donna Kowalski, Katsuyuki Hori, Koji Ishibashi, Takashi Usui and Hidetaka Kamimura
Drug Metabolism and Disposition February 2010, 38 (2) 249-259; DOI: https://doi.org/10.1124/dmd.109.029280
Tsuyoshi Minematsu
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Jennifer Lee
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Jiuhong Zha
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Selina Moy
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Donna Kowalski
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Katsuyuki Hori
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Koji Ishibashi
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Takashi Usui
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Hidetaka Kamimura
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Abstract

We investigated the 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 in in vitro and in vivo settings. First, the inhibitory effects of FK1706 (preincubation dependence, inactivation rate estimation, and reversibility) were tested using human liver microsomes. Second, the effect of repeated oral doses 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 a time-dependent and irreversible manner. The in vitro maximum inactivation rate constant (kinact) and concentration of inhibitor that gave half-maximal kinact (KI) were estimated to be 10.1 h−1 and 2050 ng/ml, respectively. In the clinical study, FK1706 produced a 2-fold increase in the 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 kinact and KI values (1.66- to 2.81-fold increases 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 that avoid drug-drug interactions.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.109.029280.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • TDI
    time-dependent inhibition
    AUC
    area under the time-concentration curve
    P450
    cytochrome P450
    FK1706
    (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
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry.

    • Received July 5, 2009.
    • Accepted November 2, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (2)
Drug Metabolism and Disposition
Vol. 38, Issue 2
1 Feb 2010
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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.…
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Research ArticleArticle

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

Tsuyoshi Minematsu, Jennifer Lee, Jiuhong Zha, Selina Moy, Donna Kowalski, Katsuyuki Hori, Koji Ishibashi, Takashi Usui and Hidetaka Kamimura
Drug Metabolism and Disposition February 1, 2010, 38 (2) 249-259; DOI: https://doi.org/10.1124/dmd.109.029280

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Research ArticleArticle

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

Tsuyoshi Minematsu, Jennifer Lee, Jiuhong Zha, Selina Moy, Donna Kowalski, Katsuyuki Hori, Koji Ishibashi, Takashi Usui and Hidetaka Kamimura
Drug Metabolism and Disposition February 1, 2010, 38 (2) 249-259; DOI: https://doi.org/10.1124/dmd.109.029280
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