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OtherDRUG METABOLISM AND DISPOSITION

Prediction of in Vivo Hepatic Metabolic Clearance of YM796 from in Vitro Data by Use of Human Liver Microsomes and Recombinant P-450 Isozymes

Takafumi Iwatsubo, Hiroshi Suzuki, Noriaki Shimada, Kan Chiba, Takashi Ishizaki, Carol E. Green, Charles A. Tyson, Tsuyoshi Yokoi, Tetsuya Kamataki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics August 1997, 282 (2) 909-919;
Takafumi Iwatsubo
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Hiroshi Suzuki
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Noriaki Shimada
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Kan Chiba
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Takashi Ishizaki
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Carol E. Green
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Charles A. Tyson
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Tsuyoshi Yokoi
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Tetsuya Kamataki
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Yuichi Sugiyama
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Abstract

The metabolic rate of (S)-(−)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro [4,5] decane-l-tartarate monohydrate (YM796), an antidementia agent, was determined by use of 12 different human liver microsomal samples. The metabolism of YM796 was shown to consist of three components; one high-affinity (K m1 = 1.67 μM), one low-affinity (K m2 = 654 μM) and a nonsaturable component. Good correlations were observed between the individual CYP3A4 content in 12 different human liver microsomal samples and kinetic parameters such as CLint, all, the high-affinity component clearance (V max1/K m1) and the low-affinity component clearance (V max2/K m2). Anti-human CYP3A4/5 antibodies inhibited the metabolism of YM796 at 1 μM by up to 75%. In addition, ketoconazole, an inhibitor of CYP3A4, inhibited YM796 metabolism by >90%. The metabolic clearance of YM796 in each of the 12 human liver microsomal samples was successfully predicted from the kinetic parameters obtained with the recombinant microsomes by taking into consideration the CYP3A4 content in each microsomal sample. Based on the CLint, allestimated from the in vitro experiments, the area under the plasma concentration-time curve after oral administration (AUCoral) of YM796 was also predicted by taking into account the hepatic blood flow rate (Q h), the unbound fraction of YM796 in human plasma (fp) and the fraction absorbed from the gut. In addition, AUCoral was determined in six healthy male volunteers. The predicted AUCoral was similar to the observed valuein vivo, which suggests that the in vitrometabolism data obtained with human liver microsomes are useful for quantitatively predicting human liver metabolism in vivo and that recombinant microsomes are also available when the particular isozyme is almost completely responsible for the metabolism of the drug, the variation in P-450 content of human liver is known and the experimental conditions such as the amount of CYP reductase and cytochrome b5 are carefully optimized to mimic the activity found in native microsomes, as for YM796.

Footnotes

  • Send reprint requests to: Yuichi Sugiyama, Ph.D., Faculty of Pharmaceutical Sciences, The University of Tokyo, 7–3-1, Hongo, Bunkyo-ku, Tokyo 113, Japan.

  • Abbreviations:
    AUCoral
    area under the plasma concentration-time curve after oral administration
    CLh
    hepatic clearance
    CLint, all
    overall intrinsic metabolic clearance (intrinsic hepatic clearance)
    CLns
    intrinsic metabolic clearance for the nonsaturable component
    Cloral
    oral clearance (= dose/AUCoral)
    CLr
    renal clearance
    CYP
    cytochrome P-450
    DN
    dispersion number
    Fh
    hepatic availability
    fp
    unbound fraction in human plasma
    Km, i
    Michaelis-Menten constant for the i-th component of the metabolic reaction
    MS
    microsomal
    Qh
    hepatic blood flow rate
    RB
    blood-to-plasma concentration ratio
    Vmax, i
    maximal metabolic rate for the i-th component of the metabolic reaction
    TLC
    thin-layer chromatography
    HPLC
    high-performance liquid chromatography
    GC
    gas chromatography
    MS-MS
    tandem mass spectrometry
    • Received December 6, 1996.
    • Accepted April 18, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 2
1 Aug 1997
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OtherDRUG METABOLISM AND DISPOSITION

Prediction of in Vivo Hepatic Metabolic Clearance of YM796 from in Vitro Data by Use of Human Liver Microsomes and Recombinant P-450 Isozymes

Takafumi Iwatsubo, Hiroshi Suzuki, Noriaki Shimada, Kan Chiba, Takashi Ishizaki, Carol E. Green, Charles A. Tyson, Tsuyoshi Yokoi, Tetsuya Kamataki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics August 1, 1997, 282 (2) 909-919;

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OtherDRUG METABOLISM AND DISPOSITION

Prediction of in Vivo Hepatic Metabolic Clearance of YM796 from in Vitro Data by Use of Human Liver Microsomes and Recombinant P-450 Isozymes

Takafumi Iwatsubo, Hiroshi Suzuki, Noriaki Shimada, Kan Chiba, Takashi Ishizaki, Carol E. Green, Charles A. Tyson, Tsuyoshi Yokoi, Tetsuya Kamataki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics August 1, 1997, 282 (2) 909-919;
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