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Drug Metabolism and Disposition Fast Forward
First published on September 2, 2004; DOI: 10.1124/dmd.104.000661

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Received for publication May 18, 2004.
Revised August 31, 2004.
Accepted for publication September 1, 2004.

Mechanism of the Drug Interaction between Valproic Acid and Carbapenem Antibiotics in Monkeys and Rats

Yoshitsugu Nakajima 1, Minoru Mizobuchi 1, Masahiro Nakamura 1, Hidetoshi Takagi 1, Haruhisa Inagaki 1, Goro Kominami 1, Masahiro Koike 1, Toshiro Yamaguchi 1*

1 SHIONOGI & CO., LTD.

* Address correspondence to: E-mail: toshiro.yamaguchi{at}shionogi.co.jp

Abstract

The Ministry of Health and Welfare, Japan banned coadministration of carbapenems such as panipenem/betamipron (PAPM), meropenem (MEPM) and valproic acid (VPA) because clinical reports have indicated that the coadministration caused seizures in epileptic patients because of lowered plasma levels of VPA. In this study, we have clarified the mechanism of the drug-drug interaction using PAPM, MEPM and Doripenem (S-4661), a newly synthesized carbapenem. In vitro experiments using monkey liver slices suggested that the apparent synthetic rate of VPA glucuronide (VPA-G) increased in the presence of carbapenems. However, no such increase was observed in the experiment using monkey liver microsome. Although no increase of UDPGA was found in monkey liver slices in the presence of carbapenems, potent inhibitory activity of carbapenems for the hydrolysis of VPA-G was found in monkey and rat liver homogenate. In vivo hydrolysis of VPA-G was clearly shown by the existence of VPA in plasma after dosing of VPA-G to rats, and its inhibition by carbapenems was also clearly shown by the negligible levels of VPA in rat plasma after coadministration of carbapenems and VPA-G. These results clearly indicate one of the important causes of drug interaction as follows: carbapenems would inhibit the hydrolytic enzyme which is involved in hydrolysis of VPA-G to VPA, resulting in decrease of plasma concentration of VPA.


Key words: antibiotics, drug-drug interactions, enterohepatic circulation, glucuronidation, UDP glucuronyltransferases


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