The influence of severity of bile flow reduction, cycloheximide, and methyl isobutyl ketone pretreatment on the kinetics of taurolithocholic acid disposition in the rat.

Pretreatment of rats with methyl isobutyl ketone (MIBK) potentiates the effect of taurolithocholic acid (TLCA) on bile flow, while cycloheximide pretreatment diminishes the cholestatic response. Experiments were performed to determine if the effects of the pretreatments were related to changes in the kinetic disposition of TLCA. Groups of rats were pretreated daily with either 7.5 mmol MIBK/kg po for 3 days or 3.55 mumol cycloheximide/kg ip for 2 days prior to an iv challenge of TLCA. Bile and blood samples were collected for 3 hr and the blood concentrations and biliary excretion of TLCA monitored. The severity of the bile flow reduction had a marked effect on the kinetic pattern of TLCA. The volume of distribution and bile disposition constant of TLCA decreased inversely with the severity of bile flow reduction, while the blood disposition constant increased. The total clearance of TLCA was not affected, but increasing the severity of the cholestasis altered the contribution of biliary and extrabiliary clearance to total clearance. The changes in the kinetics of TLCA observed in MIBK- and cycloheximide-pretreated rats were consistent with the effects the pretreatments exerted on TLCA-induced reduction in bile flow. They were interpreted to be the result of the effects of the pretreatments rather than their cause. Thus, pretreatment with MIBK and cycloheximide appears to exert a modulating effect on TLCA-induced cholestasis by mechanisms unrelated to an alteration of TLCA kinetic profile.