The hepatic metabolism and biliary and pancreatic excretion of the serine protease inhibitor camostat mesilate and its metabolites FOY-251 and GBA were studied in rats in vivo and in in sutu liver-perfusion experiments. After oral feeding (100 mg/kg) and iv infusion (5 mg/kg.h) of camostat mesilate, the original compound and both metabolites appeared in bile, but could not be detected in pancreatic juice. In plasma, only FOY-251 and GBA were detected. In the perfused rat liver, camostat mesilate (10 microM) was eliminated by 33.8% and its molar rate of degradation to FOY-251 was 25.1%. During the study period about 0.1% of camostat mesilate and FOY-251 appeared in bile. The liver perfusion of FOY-251 or GBA revealed very low hepatic extraction rates of 10.3 and 2.4%, respectively. In conclusion, the low hepatic extraction rate of camostat mesilate and its metabolites leads to high concentrations of the active metabolite FOY-251 in plasma. Camostat mesilate and its metabolites are effectively excreted into bile, but not in rat pancreatic juice.
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