RT Journal Article
SR Electronic
T1 MECHANISM OF THE DRUG INTERACTION BETWEEN VALPROIC ACID AND CARBAPENEM ANTIBIOTICS IN MONKEYS AND RATS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1383
OP 1391
DO 10.1124/dmd.104.000661
VO 32
IS 12
A1 Nakajima, Yoshitsugu
A1 Mizobuchi, Minoru
A1 Nakamura, Masahiro
A1 Takagi, Hidetoshi
A1 Inagaki, Haruhisa
A1 Kominami, Goro
A1 Koike, Masahiro
A1 Yamaguchi, Toshiro
YR 2004
UL http://dmd.aspetjournals.org/content/32/12/1383.abstract
AB 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 due to 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; (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-caboxylic acid monohydrate], 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 microsomes. Although no increase of uridine 5′-diphosphate d-glucuronic acid 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 the hydrolysis of VPA-G to VPA, resulting in a decrease of plasma concentration of VPA. The American Society for Pharmacology and Experimental Therapeutics