Abstract
Plasma levels of valproic acid (VPA) are decreased by the 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. In order to elucidate this interaction mechanism, we purified VPA-G hydrolase from human liver cytosol, in which the hydrolytic activity was mainly located. After a chromatographical purification, the VPA-G hydrolase was identified as acylpeptide hydrolase (APEH). APEH depleted 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 (DFP, DTNB, PCMB 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. β-Glucuronidase activity remained in APEH depleted cytosol, whereas the VPA-G hydrolase activity was completely abolished. Thus, either cholinesterase, carboxylesterase or β-glucuronidase in cytosol would hardly be involved in VPA-G hydrolysis. Collectively, 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.
Footnotes
- Received March 3, 2010.
- Accepted June 15, 2010.
- The American Society for Pharmacology and Experimental Therapeutics