Stereoselective Biliary Excretion of Ibuprofen and Ketoprofen and Their Glucuronides in EHBR

抄録

[Purpose] EHBR is a kind of Sprague-Dawley strain rats of which cMrp transporters is defective. As ibuprofen (IB), ketoprofen (KP) and most of other NSAIDs are partially metabolized to their glucuronides and excreted into bile by cMrp, their biliary elimination can be suppressed in EHBR. In this study, we observed the effect of the deficit on the bile excretion of IB, KP and their glucuronides S-IBG, R-IBG, S-KPG, and R-KPG in EHBR comparing with in normal SD rats. The difference in plasma concentrations of IBG or KPG between the two kinds of rats was also investigated.[Methods] Male EHBR and SD rats were used and underwent cannulation of the jugular vein and the bile duct．After the surgery, 20 mg/kg of the racemic IB or KP were administrated intravenously, followed by the collection of bile and blood samples in different time intervals and measured by HPLC methods. [Results and Discussion] The bile excretion of IB，KP and their glucuronides were obviously suppressed in EHBR. During the first 6 hr after the drug administration, the cumulative amounts of S-IBG, R-IBG, and IB excreted in bile were 18.4%, 3.0%, and 1.5%, respectively in SD rats, and 1.7%, 0.6%, and 0.2%, respectively in EHBR，and the cumulative amounts of S-KPG, R-KPG, and KP excreted in bile were 86.6%, 6.0%, and 2.3%, respectively in SD rats, and 18.5%, 1.8%, and 0.8%, respectively in EHBR. Compared with SD rats, EHBR had a higher plasma concentration of IBG or KPG. For both kinds of rats, the amount of glucuronides of S-enantiomers excreted in bile were higher than those of their antipodes. Since the excretion of IB，IBG, KP and KPG were only partially but not totally suppressed in EHBR, another transport mechanism might be exist in the excretion process besides cMrp transporters.