Changes in hepatic drug metabolism in alloxan-diabetic male rabbits

Longhurst, Penelope A.; Lacagnin, Lynn B.; Staats, D.A.; Colby, Howard D.

doi:10.1016/0006-2952(86)90341-2

Cited by 9 publications

(4 citation statements)

References 15 publications

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“…Further, convincing reports show that diabetes alters the pharmocodynamics and pharmacokinetics of drugs/xenobiotics in man and animals [19,20]. We reported that alloxan-induced diabetes-modulated cadmium [21][22][23] toxicity in rat.…”

Section: Introductionmentioning

confidence: 85%

Effect of Insulin on Arsenic Toxicity in Diabetic Rats—Liver Function Studies

Singh

Rana²

2009

Biol Trace Elem Res

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Arsenic (iAs)-induced diabetic mellitus has been debated by several workers. However, role of insulin in iAs-induced diabetes is yet to be investigated. Present report suggests that iAs promotes insulin secretion in diabetic rats and inhibits hyperglycemia. Whereas, reverse effects were recorded after insulin treatment to diabetic and iAs-treated rats. These conditions affect accumulation of iAs in liver. It decreased in diabetic and iAs-treated rats but increased after insulin treatment. Reciprocal effects were observed on serum transaminases and total bilirubin. Nevertheless, activity of glucose-6-phosphatase in the liver was stimulated by insulin treatment to diabetic and arsenic-fed rats. These results suggest that manifestations of arsenic-induced diabetes mellitus are not modulated or reversed by insulin. Observations on liver function further suggest that iAs is less toxic in diabetic rats. This protective effect has been attributed to noninsulin-dependent carbohydrate regulatory mechanisms. Diabetes certainly alters the pharmacodynamics and pharmacokinetics of iAs in rat.

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Section: Introductionmentioning

confidence: 85%

Effect of Insulin on Arsenic Toxicity in Diabetic Rats—Liver Function Studies

Singh

Rana²

2009

Biol Trace Elem Res

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“…This information must be 483 evaluated with care when trying to predict changes in humans, because the effect of diabetes on drug metabolism in animals is both gender-and speciesspecific (Longhurst et al 1986;Reinke et al 1979). It is now apparent that uncontrolled diabetes causes an overall increase in cytochrome P450 in the rat, although 2 isozymes under androgen control are markedly decreased (Favreau & Schenkman 1988).…”

Section: Biotransformationmentioning

confidence: 98%

The Effects of Diabetes Mellitus on Pharmacokinetics and Pharmacodynamics in Humans

Gwilt

Nahhas

Tracewell

1991

Clinical Pharmacokinetics

143

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The article reviews the effect of diabetes on the pharmacokinetics and pharmacodynamics of drugs in humans. For most drugs which cross the gastrointestinal wall by passive diffusion, oral absorption is unlikely to be affected by diabetes, although a delay in the absorption of tolazamide and a decrease in the extent of absorption of ampicillin have been reported. Subcutaneous absorption of insulin is more rapid in diabetic patients, whereas the intramuscular absorption of several drugs is slower. The binding of a number of drugs in the blood is reduced in diabetes, which may be due to glycosylation of plasma proteins or displacement by plasma free fatty acids, the level of which is increased in diabetic patients. Plasma concentrations of albumin and alpha 1-acid glycoprotein do not appear to be changed by the disease. The distribution of drugs with little or no binding in the blood is generally not altered, although the volume of distribution of phenazone (antipyrine) is reduced by 20% in insulin-dependent diabetes mellitus (IDDM). In contrast to animal studies, the metabolic clearance of most drugs in humans appears to be unaffected or slightly reduced by the disease. The presence of fatty liver in non-insulin-dependent diabetes mellitus (NIDDM) may contribute to a reduced hepatic clearance, whereas decreased binding in the blood may cause an increase in clearance. The effect of diabetes on hepatic blood flow in humans appears to be unknown. Diabetes affects kidney function in a significant number of diabetic patients. During the first 10 years after the onset of the disease, glomerular filtration is elevated in these patients. Thus, the renal clearance of a number of antibiotics has been shown to be increased in diabetic children. As the disease progresses, renal function is impaired and glomerular function declines from the initial elevated state. In diabetic adults the renal clearance of drugs either is comparable with that found in nondiabetic individuals or is reduced. A limited number of studies have been conducted comparing the dose-response of cardiovascular drugs in diabetic patients with that in nondiabetic controls. Decreased, increased and unchanged responses have been reported. It is apparent that in some cases an altered response may be observed for a drug when administered to a diabetic patient compared with a similar nondiabetic individual. At the present time, it is not possible to ascertain whether these studies reflect true pharmacodynamic changes or merely alterations in pharmacokinetics.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Numerous investigators have reported alterations in hepatic metabolism in response to chemical induction of diabetes mellitus with alloxan or streptozotocin in various animal species. 1,2 These agents produce hyperglycemia by chemical ablation of pancreatic islet ␤ cells with resultant hypoinsulinemia, a state analogous to insulin-dependent (type 1) diabetes mellitus in humans. 3 Changes in mixed-function oxidase activity (cytochrome P450) produced by streptozotocin and alloxan are attributed to resultant diabetic changes rather than to the chemical per se.…”

mentioning

confidence: 99%