イヌにおけるvalproic acidとpanipenemの相互作用

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  • Effect of panipenem on the pharmacokinetics of valproic acids in dogs.

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The pharmacokinetic-based drug-drug interaction between a carbapenem antibiotic, panipenem (PAPM), and an acid antiepiletic drug valproic acid (VPA), was investigated in dogs, Elimination half-lives of VPA after oral and intravenous administration of VPA at 30mg/kg after concomitant intravenous injection of PAPM at 50mg/kg decreased to about 25% and 10%, respectively, of those after administration of VPA without PAPM. Absorption of VPA after oral administration was not affected by concomitant PAPM as indicated by the fact that the Cmax and Tmax values of VPA were unchanged. The in vivo plasma-free fraction of VPA varied between 7 and 36% depending on the total plasma level, and were not affected by concomitantly administered PAPM. Renal clearance tests at a constant rate of infusion of VPA were performed in two anesthetized dogs. The steady state plasma concentrations and the rates of renal excretion of the glucuronide metabolite of VPA during simultaneous infusion of PAPM and VPA were significantly higher than those in the control period (VPA alone). In vitro UDP-glucuronosyltransferase (UDPGT) activity toward VPA was found in dog hepatic microsomes, but not in renal microsomes. Concomitant injection of meropenem also enhanced the elimination of VPA from plasma, whereas cefozopran, flomoxef, cefmetazole and cephalexin did not affect VPA pharmacokinetics. These results indicate that the enhancement on VPA elimination was specific for the carbapenem antibiotics and some metabolic activation mechanism of hepatic UDPGT might contribute to this drug-drug interaction.

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