Comparative effects of indomethacin on hepatic enzymes and histology and on serum indices of liver and kidney function in the rat.
The effects of high-dose indomethacin (three daily dose, 8.5 mg/kg ip) on pathology and histology, on serum and urine biochemistry, and on various hepatic enzyme activities were studied in rats. Hepatic cytochrome P-450 and aminopyrine N-demethylase were decreased by 52-62%, but glucuronyl transferase fell by only 22%. Hepatic glucose-6-phosphatase, aryl esterase, 6-phosphogluconate dehydrogenase and sulphotransferase remained unchanged, while glucose-6-phosphate dehydrogenase increased by 29%. There were no widespread changes in hepatic and renal pathology or histology, but noteworthy was a mild, focal, centrilobular hepatic response. By contrast, there were severe intestinal lesions: the effects on hepatic enzymes might have been partly a consequence of the intestinal damage. There was a reversible uraemia and significant decreases (20-40% below normal) in both serum albumin and protein, while serum levels of creatinine and aspartate-amino-transferase activity remained constant. A reversible N-acetyl-beta-D-glucoseaminidase (NAG) enzymuria occurred (300% above normal), but no significant proteinuria (less than 300 mg/l). Administration of 16, 16-dimethylprostaglandin F2 alpha(0.5 mg/kg iv) concomitantly with the indomethacin greatly ameliorated the intestinal lesions and prevented the decreases in hepatic drug-metabolizing enzymes. Concomitant 16,16-dimethylprostaglandin F2 alpha did not, however, influence the indomethacin-induced decreases in serum protein, albumin or NAG-enzymuria. It was concluded that indomethacin had a highly selective effect causing a decrease in hepatic cytochrome P-450, which was not accompanied by severe damage to hepatocyte structure.
D000118:Acetylglucosaminidase / Q000378:metabolism; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D007213:Indomethacin / Q000633:toxicity*; D007422:Intestines / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D007677:Kidney Function Tests; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008111:Liver Function Tests; D008297:Male; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism; D014511:Uremia / Q000139:chemically induced
D011461:Prostaglandins F, Synthetic; D012709:Serum Albumin; C022934:16,16-dimethylprostaglandin F2alpha; D003577:Cytochrome P-450 Enzyme System; D015237:Dinoprost; D005954:Glucosephosphate Dehydrogenase; D000633:Aminopyrine N-Demethylase; D014453:Glucuronosyltransferase; D000118:Acetylglucosaminidase; D007213:Indomethacin