Probenecid-associated alterations in valproate glucuronide hepatobiliary disposition: Mechanistic assessment using mathematical modeling

The complexity of processes associated with the hepatobiliary disposition o f xenobiotics may require a multiexperimental approach, including pharmacok inetic modeling, to assess mechanisms of drug interactions. The objective o f this study was to examine the disposition of valproate glucuronide (VG) i n 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 ab sence and presence of PRB (similar to 75 mug/ml). Concentrations of VPA and VG in perfusate and bile were determined at timed intervals. In the absenc e of PRB, total recovery of VPA and VG in perfusate and bile was similar to 80%; PRB significantly increased this recovery to similar to 100%, suggest ing a decrease in oxidative VPA metabolism. Similarly, pharmacokinetic mode ling of the IPL data indicated that PRB competitively inhibited formation o f oxidative VPA metabolites. PRB also significantly inhibited formation, bi liary excretion, and sinusoidal egress of VG. These observations suggest a competitive interaction between PRB and VG for transport across the canalic ular and sinusoidal membranes. Despite PRB-associated impairment of VG form ation, mathematical modeling of the data revealed that hepatocyte VG concen trations were increased by PRB, presumably due to simultaneous inhibition o f VG biliary excretion and sinusoidal egress by PRB. These results demonstr ate the utility of pharmacokinetic modeling in elucidating the mechanisms o f alteration in the hepatobiliary disposition of xenobiotics.