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OtherDRUG METABOLISM AND DISPOSITION

Prediction of Species Differences (Rats, Dogs, Humans) in theIn Vivo Metabolic Clearance of YM796 by the Liver fromIn Vitro Data

Takafumi Iwatsubo, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics November 1997, 283 (2) 462-469;
Takafumi Iwatsubo
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Hiroshi Suzuki
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Yuichi Sugiyama
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Abstract

The bioavailability after oral administration of (S)-(-)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro [4,5] decane-l-tartarate monohydrate (YM796), which is being developed as an antidementia drug, at a dose of 1 mg/kg was very low (3.4%) in rats, but considerably higher (16.1%) in dogs. The oral clearances (CLoral, Dose/AUCoral) in rats and dogs were, respectively, 300 and 18 times more than that already reported in humans. We have previously reported successful attempts to predict the in vivohepatic metabolic clearance of YM796 from in vitro data in humans. In our study, the in vitro metabolism of YM796 was determined using liver microsomes prepared from both rats and dogs and we also investigated if the species difference observedin vivo could be quantitatively reproduced in vitro. In rats, total metabolite formation could be described by single component kinetics with a Km of 13.4 μM and a Vmax of 520 nmol/min/g liver. However, in dogs, total metabolite formation could be described by three components, as also reported for humans. TheKm and Vmax values for the high-affinity, low-capacity component (Km1 and Vmax1) in dogs and humans were, respectively, 8.1 and 1.7 μM, and 10.9 and 1.2 nmol/min/g liver. The overall intrinsic metabolic clearances estimated from the in vitro studies (CLint,in vitro) for rats and dogs were 38.8 and 2.6 ml/min/g liver, respectively, being approximately 40 and 3 times more than that previously reported for humans (0.94 ml/min/g liver). The overall intrinsic hepatic clearances (CLint,in vivo) calculated from in vivo CLoral were 30.4, 3.4 and 0.73 ml/min/g liver for rats, dogs and humans, respectively, indicating that the in vivo hepatic clearance of YM796 can be predicted from in vitro metabolism data in each species. Thus, the pronounced species difference in the metabolic clearance observedin vivo can be quantitatively predicted from in vitro metabolic data using liver microsomes, and was predominantly due to the large difference in the Vmaxvalues.

Footnotes

  • Send reprint requests to: Dr.Yuichi Sugiyama, 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)
    CLint,in vitro
    overall intrinsic metabolic clearance estimated from the in vitro study
    CLint,in vivo
    overall intrinsic hepatic clearance calculated based on the in vivopharmacokinetic information
    CLns
    intrinsic metabolic clearance for the nonsaturable component
    CLoral
    oral clearance (= Dose/AUCoral)
    CLr
    renal clearance
    CLtot
    total body clearance
    CYP
    cytochrome P-450
    DN
    dispersion number
    Fa
    the fraction absorbed from the intestinal tract
    Fh
    hepatic availability
    fb
    unbound fraction in blood
    fp
    unbound fraction in plasma
    GC
    gas chromatography
    Km,i
    Michaelis-Menten constant for the i-th component of the metabolic reaction
    MS
    microsomal
    MS-MS
    tandem mass spectrometry
    Qh
    hepatic blood flow rate
    RB
    blood-to-plasma concentration ratio
    TLC
    thin-layer chromatography
    Vmax,i
    maximum metabolic rate for the i-th component of the metabolic reaction
    • Received January 29, 1997.
    • Accepted July 8, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 283, Issue 2
1 Nov 1997
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OtherDRUG METABOLISM AND DISPOSITION

Prediction of Species Differences (Rats, Dogs, Humans) in theIn Vivo Metabolic Clearance of YM796 by the Liver fromIn Vitro Data

Takafumi Iwatsubo, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 462-469;

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OtherDRUG METABOLISM AND DISPOSITION

Prediction of Species Differences (Rats, Dogs, Humans) in theIn Vivo Metabolic Clearance of YM796 by the Liver fromIn Vitro Data

Takafumi Iwatsubo, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics November 1, 1997, 283 (2) 462-469;
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