title: Hepatic and pancreatic metabolism and biliary excretion of the protease inhibitor camostat mesilate.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Ulm, FRG.
authors.forename: K
authors.initials: K
authors.lastname: Beckh
authors.forename: H
authors.initials: H
authors.lastname: Weidenbach
authors.forename: F
authors.initials: F
authors.lastname: Weidenbach
authors.forename: R
authors.initials: R
authors.lastname: Müller
authors.forename: G
authors.initials: G
authors.lastname: Adler
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000493:pharmacokinetics; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D004952:Esters; D016670:Gabexate / Q000031:analogs & derivatives*; D006146:Guanidines / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D010189:Pancreatic Juice / Q000737:chemistry / Q000378:metabolism; D010477:Perfusion; D011480:Protease Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013056:Spectrophotometry, Ultraviolet
chemical_list: D001565:Benzoates; D004952:Esters; D006146:Guanidines; D011480:Protease Inhibitors; C034532:camostat; C023856:4-guanidinobenzoate; D016670:Gabexate; C045130:4-(4-guanidinobenzoyloxy)phenylacetic acid