Drug Disposition Lilly Research Laboratories Indianapolis Indiana.
Medicinal Chemistry Lilly Research Laboratories Indianapolis Indiana.
Pharmacol Res Perspect. 2019 Jul 4;7(4):e00502. doi: 10.1002/prp2.502. eCollection 2019 Aug.
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.
药物的肠肝循环（EHC）通常是由于直接的葡萄糖醛酸化，将代谢物排泄到胆汁中，然后被肠道微生物群水解为糖苷配基，最后药物被重新吸收到体循环中。本研究的目的是确定决定犬中环己烷二酮（DPTQ）和坎格列净 EHC 的关键因素，这两种化合物通过 UDP-葡萄糖醛酸转移酶（UGT）介导的 O-烷基葡萄糖醛酸化和细胞色素 P450（P450）介导的氧化作用清除。在单次静脉给药后，比较了这两种药物在胆管插管（BDC）和完整比格犬中的药代动力学特征。在完整的狗中观察到 DPTQ 的长末端消除相，但在坎格列净中没有，而在 BDC 动物中没有观察到这种长末端半衰期，提示 DPTQ 的 EHC。胆汁、尿液和粪便中母体药物和葡萄糖醛酸代谢物的定量表明，两种药物在胆汁和尿液中的母体药物回收率低，尿液中结合代谢物的回收率低，而 BDC 犬中这些葡萄糖醛酸代谢物的胆汁排泄率低，DPTQ 则高得多。完整犬中母体药物粪便回收率增加，缺乏葡萄糖醛酸代谢物提示肠道微生物群对 DPTQ-葡萄糖醛酸苷的水解。随后对体外肝代谢和通透性特性的表征表明，UGT 代谢的肝部分、代谢物的水解以及糖苷配基的重吸收是决定 DPTQ EHC 的关键因素。
