Metabolism of pamaqueside, a cholesterol absorption inhibitor, in Long-Evans rat: effect of bile duct cannulation on absorption.
The metabolism of pamaqueside, a cholesterol absorption inhibitor, was studied in the bile duct cannulated and non-cannulated rat after an oral dose (100 mg/kg) and an i.v. dose (6 mg/kg) of [14C]pamaqueside. Faeces was the major route of excretion in all rat. Only 0.1% of the radioactivity was recovered in the urine of the non-cannulated rat. In contrast, approximately 17% of the total dose was recovered in the bile and urine in the bile duct cannulated rat. Following an i.v. dose, an almost equal percentage of radioactivity was excreted in the bile and urine of the bile duct cannulated rat. 3. The aglycone (M1) was the major metabolite in rat and was present in greater amounts in the faeces of the bile duct cannulated rat. The structural elucidation of metabolites in the bile and urine indicated that M1 was metabolized oxidatively via a novel ring opening, and the oxidative metabolites further underwent sulphate conjugation. The oxidative ring opening of pamaqueside (the cellobioside ring intact) was also observed following an i.v. dose to rat suggesting that oxidative ring opening was the major route of metabolism of saponins, at least in rat. The study demonstrated that the absorption and metabolism of pamaqueside was altered by surgical cannulation of rat.
Dalvie
D
D
Candidate Synthesis, Enhancement and Evaluation, Pfizer Central Research, Groton, CT 06340, USA. deepak_k_dalvie@groton.pfizer.com
O'Donnell
J
J
D000818:Animals; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000502:physiology* / Q000601:surgery; D002250:Carbon Radioisotopes; D002404:Catheterization; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D007408:Intestinal Absorption; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D020318:Rats, Long-Evans; D012503:Saponins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000652:urine; D013431:Sulfates / Q000378:metabolism
D002250:Carbon Radioisotopes; D012503:Saponins; D013431:Sulfates; C099629:pamaqueside