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.
Highlights
Enterohepatic circulation enterohepatic circulation (EHC)) is a process composed of a circuit of hepatic metabolism, biliary excretion, gut microbiome metabo‐ lism, followed by reabsorption from the gut back to systemic cir‐ culation.[1,2] Forty‐five drugs were identified that undergo EHC in a recent review article.[3]
The drug itself may be directly secreted into bile without undergoing metabolism; others undergo conjugation in the liver, such as glucuronidation and sulfation, the metabolites are excreted in bile, stored in gallbladder, and re‐ leased to the gut, where they undergo hydrolysis back to the par‐ ent drug by gut microbiome.[2]
A recent study investigated the fraction of hepatic metabolism fm) in dogs and suggested EHC will affect the cumulative fm estimation of drugs that are metabolized by both cytochrome P450 (P450) and UGTs in the liver, when the glucuronide metabolites are excreted into bile and hydrolyzed by gut microbiome during the process of EHC.[4]
Summary
Enterohepatic circulation EHC) is a process composed of a circuit of hepatic metabolism, biliary excretion, gut microbiome metabo‐ lism, followed by reabsorption from the gut back to systemic cir‐ culation.[1,2] Forty‐five drugs were identified that undergo EHC in a recent review article.[3]. The drug itself may be directly secreted into bile without undergoing metabolism; others undergo conjugation in the liver, such as glucuronidation and sulfation, the metabolites are excreted in bile, stored in gallbladder, and re‐ leased to the gut, where they undergo hydrolysis back to the par‐ ent drug by gut microbiome.[2]. Pharmacokinetic parameters such as half‐life (t1/2), volume of distribution (Vdss), area under the concen‐ tration‐time curve AUC) and bioavailability often are substantially affected by EHC with orally administered drugs,[2] demonstrating the importance of assessing the magnitude of EHC to model the pharmacokinetic/pharmacodynamics PK/PD) for a clinical candi‐ date in drug discovery. Given the disposition of canagliflozin has been reported for humans,[11] a comparison of the in vitro and in vivo metabolic and excretion data of canagliflozin in human to those obtained with dog was performed in order to iden‐ tify the species differences in the process of EHC
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