Abstract
The enterohepatic circulation (EHC) of drugs is often the result of the direct glucuronidation, excretion of the metabolite into bile, followed by hydrolysis to the aglycone by the gut microbiome and finally reabsorption of drug into the systemic circulation. The aim of present study to identify key factors in determining the EHC in dog for canagliflozin and DPTQ, two compounds cleared by UDP-glucuronosyltransferase (UGT) mediated O-alkyl glucuronidation and cytochrome P450 (P450) mediated oxidation. The pharmacokinetic profiles of the drugs were compared between bile duct cannulated (BDC) and intact beagle dogs after a single intravenous administration. A long terminal elimination phase was observed for DPTQ but not for canagliflozin in intact dogs, while this long terminal half-life was not seen in BDC animals, suggesting the EHC of DPTQ. Quantification of parent drugs and glucuronide metabolites in bile, urine and feces indicated low recovery of parent in bile and urine and low recovery of conjugated metabolites in urine for both drugs, while biliary excretion of these glucuronide metabolites in BDC dog were low for canagliflozin but much higher for DPTQ. The increased fecal recovery of parent drug in intact dog and the lack of glucuronide metabolites suggested the hydrolysis of DPTQ-glucuronides by gut microbiome. Subsequent characterization of in vitro hepatic metabolism and permeability properties indicated the hepatic fraction metabolized by UGT, hydrolysis of metabolites, and reabsorption of the aglycone were key factors in determining the EHC of DPTQ.