Decrease in serum levels of valproic acid during treatment with a new carbapenem, panipenem/betamipron

Nagai, Kosaku; Shimizu, Takahiro; Togo, Amadou Hamidou; Takeya, M; Yokomizo, Yuichi; Sakata, Y; Matsuishi, Toshiya; Kato, Hiroki

doi:10.1093/jac/39.2.295

Cited by 83 publications

(41 citation statements)

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“…Decline in valproate serum concentration and seizures were observed within 24 hours after concomitant administration of valproate and meropenem in our patient. The most rapid decrease of serum valproate within 24 [7] and 36 hours [6] were reported in other studies. In some other reports, this decline was observed within three to seven days after the initiation of meropenem to patients receiving valproate therapy [1].…”

Section: Discussionsupporting

confidence: 57%

Seizure worsening caused by low serum valproate levels from an interaction between valproate and meropenem

Biçer

Erdağ

Yıldırım³

et al. 2015

MMJ

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We present an interaction of meropenem with valproate in an epileptic child, leading to seizure exacerbations owing to the rapid lowering of serum valproate concentration. An increase of seizure frequency and somnolence were observed in the patient after the addition of meropenem to the treatment, and a rapid decline of valproate serum concentrations was observed after two doses of meropenem. This decline was the most likely cause of the increase in seizure frequency. The dosage of valproate was raised and meropenem was stopped. Two days later, the seizures stopped. Five days later, the serum valproate concentrations raised to three fold, and they rose to therapeutic levels four weeks later. To avoid drug interaction that reduces the serum concentration of valproate, meropenem in epileptic patients using valproate for the treatment of epilepsy should be administered cautiously. If concominant administration is essential, close observation of serum concentration of valproate and clinical course of the patient are necessary. Keywords: Carbapenems, Drug interactions, Meropenem, Seizures, Valproate ÖZETBu yazıda, meropenem ve valproat etkileşimine sekonder olarak serum valproat düzeyinin hızlı düşmesi sonucu nöbetleri alevlenen epileptik bir çocuk sunulmuştur. Hastanın tedavisine meropenem eklendikten ve iki doz kullanıldıktan sonra nöbet sıklığı ve somnolans durumunda artış ortaya çıkan hastanın serum valproat düzeyinde ani düşme görüldü. Nöbet sıklığındaki artışın valproat serum düzeyinin düşüşüne bağlı olduğu düşünüldü. Hastanın valproat dozu artırılarak meropenem tedavisi kesildikten iki gün sonra nöbetler sona erdi. Beş gün sonra serum valproat düzeyi üç katına, dört hafta sonra ise terapötik düzeylere yükseldi. Serum valproat düzeyinin düşmesine neden olan ilaç etkileşimine neden olmamak için, valproat kullanan epileptik hastalarda meropenem dikkatle uygulanmalı, iki ilacın birlikte kullanımı mutlaka gerekliyse hastanın klinik durumu ve serum valproat düzeyi yakından izlenmelidir.

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Section: Discussionsupporting

confidence: 57%

Seizure worsening caused by low serum valproate levels from an interaction between valproate and meropenem

Biçer

Erdağ

Yıldırım³

et al. 2015

MMJ

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“…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.…”

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confidence: 90%

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

Nakajima¹,

Mizobuchi²,

Nakamura³

et al. 2004

Drug Metab Dispos

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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...

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“…We found no activation of UGT1A6 by streptopmycin but found weak activity increase by ampicillin. Meanwhile, in clinical case reports, 7,25) ampicillin and cephalosporin amtoniotics did not influence on plasma VPA level. These three antibiotics (carbapenem, penicillin, and cephalosporin) have similar structure as shown in Fig.…”

Section: Discussionmentioning

confidence: 81%

“…7) VPA is excreted from the kidney after conjugation with glucuronide by UGT in the liver. In blood, VPA is the bound state with plasma protein and carbapenem antibiotics are not bound with plasma protein.…”

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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Decrease in serum levels of valproic acid during treatment with a new carbapenem, panipenem/betamipron

Cited by 83 publications

References 0 publications

Seizure worsening caused by low serum valproate levels from an interaction between valproate and meropenem

Seizure worsening caused by low serum valproate levels from an interaction between valproate and meropenem

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

In Vitro Activation of Valproate Glucuronidation by Carbapenem Antibiotics

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