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Title: Comparative effects of diabetogenic agents on hepatic drug metabolism
Authors: K. Chawlit
P. Sretarugsa
A. Thithapandha
Mahidol University
Keywords: Pharmacology, Toxicology and Pharmaceutics
Issue Date: 1-Jan-1982
Citation: Drug Metabolism and Disposition. Vol.10, No.1 (1982), 81-86
Abstract: Chemical diabetes produced in male rats by treatment with alloxan (120 mg/kg, sc), 6-aminonicotinamide (35 mg/kg, ip), streptozotocin (55 mg/kg, ip) and N-methylacetamide (6.25 ml/kg, po) significantly prolonged hexobarbital sleeping time without affecting the awakening brain barbiturate level. Pharmacokinetic studies of aminopyrine in these diabetic animals also showed an increase in plasma half-life of the drug without any change in its volume of distribution. Aminopyrine N-demethylase activity from these rats was depressed although hepatic microsomal protein and cytochrome P-450 content were unaffected. In contrast, not all of these four agents decreased the metabolism of aniline; in fact, aniline hydroxylase activity was increased by about 50% in animals treated with this dosage schedule of alloxan. In either case, however, insulin (20 units/kg, once daily for 2 days) could antagonize the chemically induced changes in liver and body weight, blood glucose, and activities of these drug-metabolizing enzymes. Glucose, insulin, and all four diabetogens had no direct effect on the drug-metabolizing enzymes in vitro. Further, this change (increase or decrease) in hepatic drug metabolism in these diabetic animals was found concurrently with a depletion of hepatic glycogen and a reduction in the circulating level of testosterone; hepatic glycogen content was reduced to approximately 30-50% of control whereas plasma testosterone concentration was reduced by about one-half. The reduction in testosterone level was not likely to be the cause for the decrease in hepatic drug metabolism, inasmuch as testosterone administration (12 mg/kg, sc, once daily for 2 days) could not restore the normal aminopyrine N-demethylase activity. Combination studies with microsomes and supernatant fractions from control and treated animals were consistent with the view that the locus of the effects of these diabetogens on hepatic drug metabolism is not cytosolic but is associated with a qualitative or quantitative change of the enzyme in the microsomal fraction itself. This possibility is also supported by the fact that sodium dodecyl sulfate/polyacrylamide gel-electrophoresis protein profiles exhibited by diabetic microsomes were different from that shown by normal microsomes.
ISSN: 00909556
Appears in Collections:Scopus 1969-1990

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