Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats.

Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats. Research Abstract Details 

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Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats. Abstract Text:

Daisuke Yamasaki,Masayuki Tsujimoto,Shigehiro Ohdo,Hisakazu Ohtani,Yasufumi Sawada,Daisuke Yamasaki,Masayuki Tsujimoto,Shigehiro Ohdo,Hisakazu Ohtani,Yasufumi Sawada,

The plasma concentration of phenytoin (PHT) is decreased by coadministration of folinate (leucovorin; LV), a folate (FA) analogue. The aim of this study was to examine the effect of LV on the pharmacokinetics of PHT in rats in vivo and to investigate the mechanism of the interaction. LV (50 mg/kg) was administered orally to rats concomitantly given intravenous PHT (50 mg/kg) to evaluate the effect of LV on the pharmacokinetics of PHT. The effect of LV on the plasma protein binding of PHT was investigated by using plasma from rats that had received oral LV. We also examined the effects of LV on the uptake of PHT into isolated rat hepatocytes and on the metabolism of PHT in isolated rat hepatocytes and rat hepatic microsomes. LV significantly increased the systemic clearance (2-fold) and liver-to-blood partition coefficient (1.24-fold) of PHT. However, it did not affect the plasma protein binding or hepatic uptake of PHT. LV increased the metabolism of PHT in isolated rat hepatocytes, with a significant 1.41-fold increase in the maximum rate of metabolism and a decrease in the Michaelis-Menten constant. On the other hand, 5-methyltetrahydrofolate (5-MTHF), a primary metabolite of LV and FA, significantly increased p-hydroxylation of PHT in rat hepatic microsomes, whereas LV and FA themselves had no effect. In conclusion, these results suggest that, in rats, LV, an FA analogue, decreases the plasma concentration of PHT by increasing the hepatic metabolism of PHT, and the increase in the PHT metabolism is, at least in part, attributable to 5-MTHF.

Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats. Publishing Authors By Initials

D Yamasaki,M Tsujimoto,S Ohdo,H Ohtani,Y Sawada,D Yamasaki,M Tsujimoto,S Ohdo,H Ohtani,Y Sawada,

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Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Therapeutic drug monitoring

VOLUME: 29

Page Numbers: 404-11

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ISSN: 0163-4356

DAY: 1

MONTH: Aug

YEAR: 2007

Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats. Information

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LANGUAGE: eng

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Grant and Affiliation Information for Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats.

AFFILIATION: Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

Country: United States

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MEDLINETA: Ther Drug Monit

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