Evidence for significant differences in microsomal drug glucuronidation by canine and human liver and kidney.
The in vitro glucuronidation of a range of structurally diverse chemicals has been studied in hepatic and renal microsomes from human donors and the beagle dog. These studies were undertaken to improve on the limited knowledge of glucuronidation by the dog and to assess its suitability as a model species for pharmacokinetic studies. In general, the compounds studied were glucuronidated severalfold more rapidly (based on intrinsic clearance estimates) by DLM than by HLM. Intrinsic clearance values for human UGT1A1 and UGT2B7 substrates were an order of magnitude higher in DLM than in HLM (e.g., gemfibrozil: 31 microl/min/mg versus 3.0 microl/min/mg; ketoprofen: 2.4 microl/min/mg versus 0.2 microl/min/mg). There were also drug-specific differences. HLM readily glucuronidated propofol (2.4 microl/min/mg) whereas DLM appeared unable to glucuronidate this drug directly. Regioselective differences in morphine glucuronidation were also apparent. Human kidney microsomes catalyzed the glucuronidation of many xenobiotics, although glucuronidation of the endobiotic 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 significant differences in the glucuronidation of xenobiotics by microsomes from the livers and kidneys of human and dog and should be confirmed using a larger panel of tissues from individual dogs. Early knowledge of the relative rates of in vitro glucuronidation, the UGTs responsible for drug glucuronidation, and their tissue distribution in different species could assist the design and analysis of preclinical pharmacokinetic and safety evaluation studies.
Soars
M G
MG
Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, Dundee, DD1 9SY, Scotland, UK.
Riley
R J
RJ
Findlay
K A
KA
Coffey
M J
MJ
Burchell
B
B
D000328:Adult; D015113:Androstane-3,17-diol / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D004285:Dogs; D005260:Female; D005665:Furosemide / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D015248:Gemfibrozil / Q000378:metabolism / Q000493:pharmacokinetics; D005966:Glucuronidase / Q000378:metabolism; D020719:Glucuronides / Q000096:biosynthesis*; D006801:Humans; D007660:Ketoprofen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008875:Middle Aged; D023421:Models, Animal; D015742:Propofol / Q000378:metabolism / Q000493:pharmacokinetics; D013045:Species Specificity
D020719:Glucuronides; D015113:Androstane-3,17-diol; C028895:androstane-3,17-diol glucuronide; C036234:furosemide glucuronide; C044223:ketoprofen glucuronide; D005665:Furosemide; D007660:Ketoprofen; D005966:Glucuronidase; D015248:Gemfibrozil; D015742:Propofol