In Vitro Activation of Valproate Glucuronidation by Carbapenem Antibiotics

Abstract

The serum concentration of valproic acid (VPA) in epilepsy patients decreased by the administration of carbapenem antibiotics, such as meropenem, panipenem or imipenem, to a sub-therapeutic level. Studies to explain the decrease were carried out using almost rats by the following steps: absorption of VPA in the intestine, glucuronidation in the liver, disposition in blood and renal excretion. It is difficult to consider the inhibition of intestinal absorption, because carbapenem antibiotics are intravenously administered and do not reach the intestine at an effective concentration. The liver is the key organ for the decrease of VPA concentration by carbapenem antibiotics, because it has been reported that no decrease of the VPA level by carbapenem was found in hepatectomized rats. The most likely mechanism in liver is the activation of UDP-glucuronosyltransferase by carbapenem antibiotics. We found a 35% increase of VPA-glucuronidation activity by the pre-incubation of human liver microsomes with meropenem. We estimated that this increase fully compensates for the decrease of serum VPA level by carbapenem antibiotics in patients. Meanwhile, we could not find the in vitro activation of CYP2A6, CYP3A4, P-glycoprotein (P-gp, MDR1) and Multidrug resistance-associated protein 2 by pre-incubation with carbapenem antibiotics. Thus, we considered that the activation of VPA glucuronidation by carbapenem antibiotics is a key point in the decrease of plasma VPA level.

In Vitro Susceptibility of Mycobacterium tuberculosis Isolates to an Oral Carbapenem Alone or in Combination with β-Lactamase Inhibitors

“…Fortunately, for patients with infectious diseases, TBM is available without cilastatin, which blocks the hydrolysis of carbapenems in kidneys, owing to the stability to dehydropeptidase 1 (drug's interview form, Meiji Seika Pharma Co., Ltd., Japan). Additionally, TBM has been reported to scarcely interact with CYP3A4 and CYP2B6 (28,29). More importantly, TBM has been proved to exhibit good distribution into the pulmonary epithelial lining fluid in an animal model, which allows TBM to be used for lung disease (28).…”

Decrease in serum valproic acid levels during treatment with ertapenem

“…It has been reported that P-glycoprotein and multidrugresistance-associated protein 2 might play a role in the renal excretion of valproic acid glucuronide. 22 However, Mori and Mizutani 22 argued that the activation of P-glycoprotein and multidrug-resistance-associated protein 2 for transport of valproic acid glucuronide could not be found by preincubation with carbapenem in vitro. Therefore, other transporters might be responsible for excreting valproic acid glucuronide from the kidneys.…”

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.…”