Effects of model traumatic injury on hepatic drug metabolism in the rat. IV. Glucuronidation.
A previously validated small mammal trauma model, hind-limb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on hepatic glucuronidation activity. As was previously observed with hepatic oxidative drug metabolism, model trauma resulted in a significant decrease in the in vivo glucuronidation of chloramphenicol, with a 23% drop in clearance of this drug. The effect on in vivo pharmacokinetics appeared to result from a complex interaction between trauma's differential influences on conjugating enzyme(s), deconjugating enzyme(s), and hepatic UDP-glucuronic acid levels, as well as the relative physiological importance of these variables. Hepatic UDP-glucuronyltransferase activities towards both p-nitrophenol and chloramphenicol were elevated (44-54%) after model injury when measured in native hepatic microsomes. However, microsomes which had been "activated" by treatment with Triton X-100 showed no significant difference between control and traumatized animals. Serum beta-glucuronidase activities were elevated by 58%, while hepatic beta-glucuronidase rose by about 16%. Nevertheless, in vivo deconjugation showed no significant change. Model trauma also resulted in a 46% decrease in hepatic UDP-glucuronic acid content. Thus, the observed post-traumatic depression of in vivo chloramphenicol glucuronidation could be due either to a diminished availability of a necessary cofactor (UDP-glucuronic acid) or to an alteration in enzyme kinetics or function in vivo.
Griffeth
L K
LK
Rosen
G M
GM
Rauckman
E J
EJ
D000818:Animals; D001012:Aorta, Abdominal / Q000293:injuries; D002701:Chloramphenicol / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005965:Glucuronates / Q000378:metabolism*; D005966:Glucuronidase / Q000097:blood; D014453:Glucuronosyltransferase / Q000378:metabolism; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism; D007700:Kinetics; D008026:Ligation; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D020113:Phenolphthalein; D010635:Phenolphthaleins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism; D014947:Wounds and Injuries / Q000201:enzymology / Q000378:metabolism*
D005965:Glucuronates; D004364:Pharmaceutical Preparations; D010635:Phenolphthaleins; C016651:phenolphthalein glucuronide; D014535:Uridine Diphosphate Glucuronic Acid; D002701:Chloramphenicol; D020113:Phenolphthalein; D014453:Glucuronosyltransferase; D005966:Glucuronidase