Increased erythrocyte distribution of valproic acid in pharmacokinetic interaction with carbapenem antibiotics in rat and human

Omoda, Kei; Murakami, Teruo; Yumoto, Ryoko; Nagai, Junya; Maeda, Yorinobu; Kiribayashi, Yoshie; Takano, Mikihisa

doi:10.1002/jps.20338

Cited by 34 publications

(19 citation statements)

References 28 publications

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“…In addition, the biliary concentrations of carbapenems in human are less than those of other ␤-lactam antibiotics, which have been reported not to interact with VPA (Thomas et al, 1981;Shiramatsu et al, 1988;Morimoto et al, 1991;Granai et al, 1992;De Turck et al, 1998;Yamagata et al, 1998), supporting the fact that the interaction at the enterohepatic circulation process would be improbable in humans. As to the blood cell distribution process, Omoda et al (2005) reported that the blood levels of VPA were not changed when the plasma level was decreased after intravenous administration of VPA with carbapenems in rats. However, both the blood and plasma levels of VPA were decreased in patients (Omoda et al, 2005); therefore, this mechanism does not contribute to the interaction in humans.…”

Section: Discussionmentioning

confidence: 99%

“…As to the blood cell distribution process, Omoda et al (2005) reported that the blood levels of VPA were not changed when the plasma level was decreased after intravenous administration of VPA with carbapenems in rats. However, both the blood and plasma levels of VPA were decreased in patients (Omoda et al, 2005); therefore, this mechanism does not contribute to the interaction in humans. Thus, the inhibition of VPA-G hydrolysis in the liver is the most plausible mechanism of the interaction of VPA with carbapenems in humans at present.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Suzuki¹,

Yamamura²,

Ogura³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Plasma levels of valproic acid (VPA) are decreased by concomitant use with carbapenem antibiotics, such as panipenem (PAPM). One of the plausible mechanisms of this interaction is the inhibition of VPA glucuronide (VPA-G) hydrolysis by carbapenems in the liver. To elucidate this interaction mechanism, we purified VPA-G hydrolase from human liver cytosol, in which the hydrolytic activity was mainly located. After chromatographic purification, the VPA-G hydrolase was identified as acylpeptide hydrolase (APEH). APEHdepleted cytosol, prepared by an immunodepletion method, completely lacked the hydrolytic activity. These results demonstrate that APEH is a single enzyme involved in PAPM-sensitive VPA-G hydrolysis in cytosol. In addition, the hydrolytic activity of recombinant human APEH was inhibited by PAPM and the inhibition profile by typical esterase inhibitors (diisopropyl fluorophosphate, 5,5-dithiobis(2-nitrobenzoic acid), p-chloromercuribenzoic acid, and D-saccharic acid 1,4-lactone) was similar to that of human liver cytosol. Cytosolic VPA-G hydrolase activity was slightly inhibited by cholinesterase and carboxylesterase inhibitors. ␤-Glucuronidase activity remained in APEH-depleted cytosol, whereas VPA-G hydrolase activity was completely abolished. Thus, either cholinesterase, carboxylesterase, or ␤-glucuronidase in cytosol would not be involved in VPA-G hydrolysis. Taken together, APEH plays a major role in the PAPM-sensitive VPA-G hydrolysis in the liver. These findings suggest that APEH could be a key enzyme for the drug interaction of VPA with carbapenems via VPA-G hydrolysis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Suzuki¹,

Yamamura²,

Ogura³

et al. 2010

Drug Metab Dispos

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Masuo

Ito

Yamamoto³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Serum concentrations of valproic acid (VPA) are markedly decreased by coadministration of carbapenem antibiotics (CBPMs). Although inhibition of deconjugation of VPA-glucuronide (VPA-G) to VPA by CBPMs has been proposed as one of the mechanisms to account for this drug-drug interaction, little information is available on the mode of inhibition. In the present study, we characterized the enzyme involved in the deconjugation of VPA-G by using human and rat liver cytosol. It is suggested that 1) deconjugation activity inhibited by CBPMs may be selective for VPA-G, 2) deconjugation of VPA-G may be mediated by enzyme(s) other than ␤-glucuronidase, and 3) the irreversible inactivation may be responsible for the inhibition of deconjugation of VPA-G by CBPMs. Finally, the kinetic parameters for inactivation (K app and k inact ) were determined for four CBPMs of diverse structure from in vitro experiments. Based on the results of simulation analyses with these parameters and the degradation rate constant of the putative VPA-G deconjugation enzyme obtained from experiments using rats, it is probable that the deconjugation enzyme for VPA-G in the liver is rapidly and mostly inactivated by these CBPMs under clinical situations.

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“…Studies to explain the decrease were carried out using almost rats by the following steps (Table 1): [8][9][10][11][12][13][14][15] absorption of VPA in the intestine, glucuronidation in the liver, disposition in blood and renal excretion. In the intestine of absorption step, there are two points: inhibition of the intestinal transporter for VPA absorption …”

Section: Introductionmentioning

confidence: 99%

In Vitro Activation of Valproate Glucuronidation by Carbapenem Antibiotics

Mori

Mizutani

2007

JOURNAL OF HEALTH SCIENCE

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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.

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Increased erythrocyte distribution of valproic acid in pharmacokinetic interaction with carbapenem antibiotics in rat and human

Cited by 34 publications

References 28 publications

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

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

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

In Vitro Activation of Valproate Glucuronidation by Carbapenem Antibiotics

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