What is the proposed mechanism by which carbapenem antibiotics decrease serum valproic acid concentrations?

Carbapenems, like ertapenem and meropenem, and to a lesser extent imipenem/cilistatin, inhibit acylpeptide hydrolase in hepatocytes. This enzyme is responsible for deconjugating the glucuronic acid group from valproate acid glucuronide (VPAg). Inhibition of VPAg deconjugation leads to increased VPAg clearance in bile, decreased valproic acid (VPA) enterohepatic recirculation, and, thus, decreased serum VPA concentrations.

  1. C.-C. Wu, et al. The Effect of Different Carbapenem Antibiotics (Ertapenem, Imipenem/ Cilastatin, and Meropenem) on Serum Valproic Acid Concentrations. Ther Drug Monit, vol. 38, no. 5, pp. 587–592, 2016, doi: 10.1097/ FTD.000000000000031 2. Suzuki, E, et al. Inhibition mechanism of carbapenem antibiotics on acylpeptide hydrolase, a key enzyme in the interaction with valproic acid. Xenobiotica. 2011 Nov;41(11):958-63. PMID: 21770850 DOI: 10.3109/00498254.2011.596582 3. Masuo Y, et al. Characterization of Inhibitory Effect of Carbapenem Antibiotics on the Deconjugation of Valproic Acid Glucuronide. Drug metabolism and disposition, 2010-10, Vol.38 (10), p.1828-1835. doi:10.1124/dmd.110.034231

Contributed by Bryan Kuhn, PharmD DABAT

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