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

Abstract

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 due to lowered plasma levels of VPA. In this study, we have clarified the mechanism of the drug-drug interaction using PAPM 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 Dglucuronic 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 increased incidence of convulsions or epileptic fits due to interaction between carbapenem antibiotics, such as panipenem/betamipron (PAPM) and meropenem (MEPM), and the antiepileptic valproic acid (VPA) was first reported clinically in 1997 (Nagai et al., 1997). Both PAPM and MEPM reduced the plasma concentration of concomitantly administered VPA, which resulted in an insufficient concentration to prevent epileptic fit. This led to prohibition of the concomitant use of carbapenem antibiotics and VPA being added to the Information on Adverse Reactions to Drugs from the Ministry of Welfare in Japan in 1996. To clarify the mechanism of this drug interaction, many studies have been conducted, but the mechanism is still not clear. (Fig. 1), is a carbapenem antibiotic newly developed by Shionogi Co. Ltd. Because its structure is similar to that of MEPM, there is a possibility of a similar drug interaction; we therefore studied the drug interactions between carbapenems, including S-4661 and VPA, and their mechanism, using in vivo and in vitro methods with monkeys and rats. Materials and MethodsChemicals. VPA (sodium valproate) was supplied by Sigma-Aldrich (St. Louis, MO). [Carbonyl-14 C]-VPA (55 mCi/mmol, 99% pure by thin-layer chromatography) was supplied by Muromachi Chemical Co. (Tokyo, Japan). Doripenem (S-4661) was synthesized by Shionogi Research Laboratories. PAPM was supplied by Sankyo Co. Ltd. (Tokyo, Japan). MEPM was supplied by Sumitomo Pharmaceutical Co. (Osaka, Japan). All other chemicals were of analytical grade.14 C-VPA-G was extracted with methanol from SEP-PAK C18 in which urine and bile, obtained after intravenous administ...

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

“…These activities were inhibited by MEPM (Fig. 2, A and B) as reported previously (Nakajima et al, 2004;Nakamura et al, 2008). 4-MUG and MFA-G were used as authentic substrates to examine whether MEPM inhibits the deconjugation of other glucuronides.…”

“…It can also be concluded that the putative enzyme is pH-sensitive but insensitive to SL. Concerning the subcellular localization of VPA-G deconjugation activity, it is reported that the activity is higher in the dmd.aspetjournals.org liver cytosol fraction than in the liver microsome fraction (Nakajima et al, 2004;Nakamura et al, 2008), where ␤-glucuronidase is enriched (Medda and Swank, 1985;Shipley et al, 1993). Considering the inhibitor sensitivity and subcellular localization of the activity, it is not likely that ␤-glucuronidase is the predominant enzyme involved in the deconjugation of VPA-G. VPAGase may be relatively selective for VPA-G, because it is not involved in the deconjugation of other glucuronide conjugates, including 4-MUG and MFA-G (Fig.…”

“…For mechanisms 4 and 5, it is difficult to explain the selectivity of the interaction between VPA and CBPMs and also the rapid effect of CBPMs on the plasma concentrations of VPA. In addition to the previously described mechanisms, Nakajima et al (2004) showed that the deconjugation activity of VPA-G in rat liver cytosol was inhibited by doripenem (DRPM) and also demonstrated that deconjugation clearance of VPA-G calculated from rat in vivo studies was significantly decreased during coadministration of DRPM. Nakamura et al (2008) showed that deconjugation of VPA-G in human liver cytosol was also completely inhibited by saccharic acid 1,4-lactone (SL), a classic ␤-glucuronidase inhibitor.…”

“…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.…”

A Review of Doripenem for the Treatment of Serious Bacterial Infections

“…Reduction in valproic acid is a carbapenem class phenomenon thought to involve inhibiting the hydrolysis of valproic acid glucuronide to valproic acid. 130 Plasma concentrations of valproic acid are reduced by coadministration of doripenem. Reduction in serum valproic acid concentrations to below the therapeutic concentration range (50 to 100 µg/mL) was observed by 12 hours after initiation of doripenem in healthy subjects coadministered both drugs.…”