Inhibition by carbapenem antibiotic imipenem of intestinal absorption of valproic acid in rats

Abstract

The concomitant use of carbapenem antibiotics with valproic acid has been prohibited because panipenem induced a decrease in plasma concentration of valproic acid in epileptic patients during valproic acid therapy. To clarify the possible mechanism of the carbapenem-valproic acid interaction, we investigated the effect of imipenem on the pharmacokinetic behaviour of valproic acid in rats. Co-administration of imipenem (30 mg kg(-1), i.v.) induced a decrease in the peak plasma concentration of valproic acid after oral administration. However, the imipenem-induced decrease in plasma concentrations of valproic acid was not observed within 60 min after intravenous injection of valproic acid. By utilizing in-situ vascular and luminal perfused small intestine, it was confirmed that absorption of valproic acid from the luminal to the vascular perfusate was decreased in the presence of imipenem (0.5 mM) in the vascular perfusate. The everted gut sac method was used to determine the effect of imipenem on active transport of valproic acid. The accumulation of valproic acid on the serosal side of the intestinal sac against the concentration gradient was reduced by lactic acid that inhibits the carrier-mediated transport of valproic acid across the intestinal brush-border membrane. However, imipenem did not affect the active transport of valproic acid. Therefore, the inhibition by imipenem of valproic acid absorption may be caused by a mechanism different from that of lactic acid. In conclusion, imipenem inhibits the intestinal absorption of valproic acid, which contributes to the decrease in plasma concentration of valproic acid after oral administration.

Identification of Valproic Acid Glucuronide Hydrolase As a Key Enzyme for the Interaction of Valproic Acid with Carbapenem Antibiotics

“…In contrast, the other three proposed mechanisms, namely, 1) interaction at intestinal absorption process, 2) interaction at enterohepatic circulation process, and 3) interaction at blood cell distribution process (Mori et al, 2007), are less likely in humans than the interaction at the VPA-G hydrolysis process. Torii et al (2001) reported that the C max and area under the curve of VPA were decreased by 50 to 60% after oral administration of VPA with imipenem and PAPM treatment in rats, suggesting that the intestinal absorption of VPA might be inhibited by carbapenems. However, the plasma level of VPA was also decreased at later time points even after intravenous administration of VPA with the carbapenems.…”

“…Some mechanisms related to absorption, distribution, and metabolism of VPA have been proposed (Kojima et al, 1998;Yamamura et al, 1999;Torii et al, 2001;Nakajima et al, 2004;Omoda et al, 2005). Among them, metabolism in the liver has been considered to be the most important for interaction, based on the following findings.…”

Decrease in serum valproic acid levels during treatment with ertapenem

“…Torii et al 19 proposed that the inhibition of intestinal absorption of valproic acid by carbapenem antibiotics might be a mechanism for the drug interaction in rats. By utilizing the in situ vascular and luAm J Health-Syst Pharm-Vol 67 Aug 1, 2010 minal perfused small intestine, the absorption of valproic acid from the luminal to the vascular perfusate was confirmed to be decreased in the presence of imipenem.…”

Characterization of Inhibitory Effect of Carbapenem Antibiotics on the Deconjugation of Valproic Acid Glucuronide

“…Concerning the interaction between VPA and CBPMs, the following mechanisms have been proposed: 1) inhibition of intestinal VPA absorption by CBPMs (Torii et al, 2001(Torii et al, , 2002, 2) interruption of enterohepatic circulation of VPA by CBPMs (Kojima et al, 1998), 3) increased partition of VPA into erythrocytes by CBPMs (Omoda et al, 2005;Ogawa et al, 2006), 4) elevation of UDP-GA levels by CBPMs (Yamamura et al, 1999(Yamamura et al, , 2000, 5) induction of UGT by CBPMs (Mori and Mizutani, 2007), and 6) inhibition of deconjugation of VPA-glucuronide (VPA-G) by CBPMs (Nakajima et al, 2004;Nakamura et al, 2008). However, most of the previously proposed mechanisms (mechanisms 1-5) may not solely explain the interaction observed under clinical conditions for the following reasons: with mechanism 1, the interaction observed after intravenous administration of VPA (Clause et al, 2005;Coves-Orts et al, 2005;Spriet et al, 2007) cannot be accounted for.…”