Evidence for significant differences in microsomal drug glucuronidation bycanine and human liver and kidney

The in vitro glucuronidation of a range of structurally diverse chemicals h as been studied in hepatic and renal microsomes from human donors and the b eagle dog. These studies were undertaken to improve on the limited knowledg e of glucuronidation by the dog and to assess its suitability as a model sp ecies for pharmacokinetic studies. In general, the compounds studied were g lucuronidated severalfold more rapidly (based on intrinsic clearance estima tes) by DLM than by HLM. Intrinsic clearance values for human UGT1A1 and UG T2B7 substrates were an order of magnitude higher in DLM than in HLM (e.g., gemfibrozil: 31 mul/min/mg versus 3.0 mul/min/mg; ketoprofen: 2.4 mul/min/ mg versus 0.2 mul/min/mg). There were also drug-specific differences. HLM r eadily glucuronidated propofol (2.4 mul/min/mg) whereas DLM appeared unable to glucuronidate this drug directly. Regioselective differences in morphin e glucuronidation were also apparent. Human kidney microsomes catalyzed the glucuronidation of many xenobiotics, although glucuronidation of the endob iotic bilirubin was not detectable in this tissue. In direct contrast, dog kidney microsomes glucuronidated bilirubin only (no glucuronidation of all other xenobiotics was detected). These preliminary studies indicated signif icant differences in the glucuronidation of xenobiotics by microsomes from the livers and kidneys of human and dog and should be confirmed using a lar ger panel of tissues from individual dogs. Early knowledge of the relative rates of in vitro glucuronidation, the UGTs responsible for drug glucuronid ation, and their tissue distribution in different species could assist the design and analysis of preclinical pharmacokinetic and safety evaluation st udies.