Probenecid-associated alterations in valproate glucuronide hepatobiliary disposition: mechanistic assessment using mathematical modeling.
The complexity of processes associated with the hepatobiliary disposition of xenobiotics may require a multiexperimental approach, including pharmacokinetic modeling, to assess mechanisms of drug interactions. The objective of this study was to examine the disposition of valproate glucuronide (VG) in the rat isolated perfused liver (IPL), and to determine the mechanisms of interaction with probenecid (PRB). Livers were isolated and perfused with standard techniques, and valproate (VPA) (20 mg) was administered in the absence and presence of PRB (approximately 75 microg/ml). Concentrations of VPA and VG in perfusate and bile were determined at timed intervals. In the absence of PRB, total recovery of VPA and VG in perfusate and bile was approximately 80%; PRB significantly increased this recovery to approximately 100%, suggesting a decrease in oxidative VPA metabolism. Similarly, pharmacokinetic modeling of the IPL data indicated that PRB competitively inhibited formation of oxidative VPA metabolites. PRB also significantly inhibited formation, biliary excretion, and sinusoidal egress of VG. These observations suggest a competitive interaction between PRB and VG for transport across the canalicular and sinusoidal membranes. Despite PRB-associated impairment of VG formation, mathematical modeling of the data revealed that hepatocyte VG concentrations were increased by PRB, presumably due to simultaneous inhibition of VG biliary excretion and sinusoidal egress by PRB. These results demonstrate the utility of pharmacokinetic modeling in elucidating the mechanisms of alteration in the hepatobiliary disposition of xenobiotics.