In vivoinhibition of acylpeptide hydrolase by carbapenem antibiotics causes the decrease of plasma concentration of valproic acid in dogs

Abstract

1. Our previous in vitro studies suggest that inhibition of the acylpeptide hydrolase (APEH) activity as valproic acid glucuronide (VPA-G) hydrolase by carbapenems in human liver cytosol is a key process for clinical drug-drug interaction (DDI) of valproic acid (VPA) with carbapenems. Here, we investigated whether in vivo DDI of VPA with meropenem (MEPM) was caused via inhibition of APEH in dogs. 2. More rapid decrease of plasma VPA levels and increased urinary excretion of VPA-G were observed after co-administration with MEPM compared with those after without co-administration, whereas the plasma level and bile excretion of VPA-G showed no change. 3. Dog VPA-G hydrolase activity, inhibited by carbapenems, was mainly located in cytosol from both the liver and kidney. APEH-immunodepleted cytosols lacked VPA-G hydrolase activity. Hepatic and renal APEH activity was negligible even at 24 h after dosing of MEPM to a dog. 4. In conclusion, DDI of VPA with carbapenems in dogs is caused by long-lasting inhibition of APEH-mediated VPA-G hydrolysis by carbapenems, which could explain the delayed recovery of plasma VPA levels to the therapeutic window even after discontinuation of carbapenems in humans.

Drug-drug interaction between valproic acid and meropenem: a retrospective analysis of electronic medical records from neurosurgery inpatients

“…The exact mechanism of this drug interaction is controversial, there are several possible assumptions: 1) decrease in VPA intestinal absorption and enterohepatic circulation; 2) increase in synthesis and inhibition in hydrolysis of VPA‐G; 3) inhibition in VPA efflux from erythrocytes; 4) elevation in urinary excretion of VPA‐G . Till now, the most possible putative mechanism in this interaction is assumed to be inhibition in APEH activity and hence increased VPA‐G urinary excretion due to decreased VPA‐G hydrolysis . Several anticonvulsant drugs, which include phenytoin, phenobarbital, and carbamazepine, are also reported to have significant influence on VPA metabolism.…”

“…Several studies have demonstrated that VPA‐G, the most important metabolite of VPA, can be hydrolyzed back to VPA by APEH exclusively . Carbapenem antibiotics can inhibit APEH activity in an irreversible manner, which leads to an increase in urinary excretion of VPA‐G and eventually makes the decreases of VPA plasma concentration . Our previous study have also indicated that concomitant use of MEPM resulted in an increase in urinary excretion of VPA‐G in Chinese epilepsy patients .…”

“…A series of reports have indicated that concomitant use of MEPM can decrease VPA plasma concentration rapidly . The exact mechanism of this drug interaction is controversial . Decreased VPA‐G deglucuronidation due to inhibition of acylpeptide hydrolase (APEH) by carbapenem antibiotics may be the key mechanism in this drug–drug interaction …”

“…The exact mechanism of this drug interaction is controversial . Decreased VPA‐G deglucuronidation due to inhibition of acylpeptide hydrolase (APEH) by carbapenem antibiotics may be the key mechanism in this drug–drug interaction …”

Carbapenems and valproate: A consumptive relationship

“…11 Although in our case series all patients received meropenem therapy, we note that all carbapenem antibiotics, including panipenem, tebipenem, ertapenem and imipenem, have a similar depleting effect on serum VPA levels. [12][13][14][15]…”