Comparative Analysis of In Vitro and In Vivo Pharmacokinetic Parameters Related to Individual Variability of GTS-21 in Canine

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Abstract

  To clarify the cause of the canine individual variability in plasma concentration after oral administration of GTS-21, we evaluated <i>in vitro</i> the metabolism to 4-OH-GTS-21 in liver microsomes of the same individuals from <i>in vivo</i> pharmacokinetic study. First, we applied to the Michaelis-Menten kinetic parameters to a dispersion model, and compared hepatic availability (<i>F</i><sub>H</sub>) and hepatic clearance (<i>CL</i><sub>H</sub>) values from <i>in vitro</i> with bioavailability (<i>F</i>), hepatic plasma flow (<i>Q</i><sub>PH</sub>), and plasma clearance (<i>CL</i><sub>P</sub>) values from <i>in vivo</i>. The ratios of <i>CL</i><sub>H</sub> to <i>Q</i><sub>PH</sub> were ranged 0.74 to 0.94, suggesting that GTS-21 is a hepatic plasma flow-limiting drug. A significant correlation of <i>F</i><sub>H</sub> and <i>F</i> in the four dogs (<i>r</i>=0.995, <i>p</i>=0.005) indicates that the variability is predominantly caused by GTS-21 <i>O</i>4-demethylase activity. Second, we specified the cytochrome P450 (CYP) enzymes that are involved with the metabolism by chemical inhibition. α-Naphthoflavone, furafylline, quinidine, quinine, and troleandomycin significantly inhibited GTS-21 <i>O</i>4-demethylase activity. Thus CYP1A, CYP2D15, and CYP3A12 were involved with <i>O</i>4-demethylation. The variability in control activity decreased on addition of α-naphthoflavone and furafylline. Third, we quantified the contents of CYP1A and CYP3A12 by enzyme-linked immunosorbent assay. The content of CYP1A was consistent with GTS-21 <i>O</i>4-demethylase activity. We concluded that canine liver CYP1A causes the individual variability in GTS-21 plasma concentration after oral administration.<br>

Journal

  • Drug Metabolism and Pharmacokinetics

    Drug Metabolism and Pharmacokinetics 17(1), 75-82, 2002-03-29

    The Japanese Society for the Study of Xenobiotics

References:  26

Codes

  • NII Article ID (NAID)
    10008198146
  • NII NACSIS-CAT ID (NCID)
    AA1162652X
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    09161139
  • Data Source
    CJP  J-STAGE 
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