The effect of carbapenem antibiotics on plasma concentrations of valproic acid.
OBJECTIVE
To critically evaluate the mechanisms of the interaction between valproic acid and carbapenem antibiotics.


METHODS
A PubMed search (January 1971-June 2009) was performed to identify literature on the interaction between valproic acid and carbapenem antibiotics. Additional references were identified through review of bibliographies of identified articles.


METHODS
Data on the mechanisms of the interaction between valproic acid and carbapenem antibiotics were extracted from identified references that were published in English.


RESULTS
Valproic acid plasma concentrations fall markedly during concomitant administration with carbapenem antibiotics due to a combination of absorption, distribution, and metabolism mechanisms. Carbapenems appear to inhibit the intestinal transporter of valproic acid, thereby reducing absorption of orally administered valproic acid. In vivo experiments in rats demonstrate a 57% reduction in absorption of orally administered valproic acid in the presence of imipenem. Follow-up studies in Caco-2 cells suggest that the inhibition probably occurs at the basolateral membrane. In addition, enterohepatic recycling of valproic acid may be diminished due to carbapenem activity against gut flora producing beta-glucuronidase. When rabbits and rats were given intravenous valproic acid-glucuronide, the glucuronide metabolite of valproic acid, 50-90% of the conversion back into valproic acid was inhibited in the presence of a carbapenem. An increase in erythrocyte distribution of valproic acid has also been observed in the presence of carbapenems. After intravenous administration of a carbapenem and valproic acid, valproic acid plasma concentrations fell in the presence of a carbapenem, yet whole blood concentrations of valproic acid did not change significantly. Follow-up studies suggest that the mechanism of this distribution shift is that multidrug resistance proteins on adenosine triphosphate-binding cassette transporters on erythrocyte membranes are inhibited by carbapenems. Thus, valproic acid is not effluxed out of the erythrocytes. Finally, carbapenems may enhance glucuronidation of valproic acid by increasing UDP-glucuronic acid levels. In rats, UDP-glucuronic acid levels increased by 1.7-fold in the presence of panipenem, which was proportionate to the increase in valproic acid-glucuronide formation.


CONCLUSIONS
Published data demonstrate a serious and complex interaction between valproic acid and carbapenem antibiotics. Coadministration should be avoided, but if no other antibiotic therapies exist, it is imperative to monitor valproic acid concentrations more frequently. Clinicians should anticipate higher doses of valproic acid to maintain therapeutic serum concentrations during coadministration and subsequent dose reductions upon discontinuation of the carbapenem antibiotic.
Mancl
Erin E
EE
Division of Pharmacy Practice, School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.
Gidal
Barry E
BE
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics; D001692:Biological Transport / Q000187:drug effects; D015780:Carbapenems / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D011817:Rabbits; D051381:Rats; D014018:Tissue Distribution; D014635:Valproic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D015780:Carbapenems; D014635:Valproic Acid