HEPATIC DRUG METABOLISM IS INCREASED IN POORLY CONTROLLED INSULIN DEPENDENT DIABETES MELLITUS (IDDM)

Abstract

In addition to increased glycosylation of hemoglobin, abnormalities of other heme proteins such as cytochrome P-450 might also occur in IDDM. We reported previously that cytochrome P-450 dependent drug metabolism is altered In IDDM using antipyrine (AP) as marker drug. AP is a reliable measure of hepatic drug metabolism. Its elimination from plasma is largely determined by hepatic drug oxidizing enzyme capacity. AP kinetics and urinary excretion of AP metabolites were measured in 14 patients (8-21 years) with IDDM in poor control (nl renal function) and compared to age matched controls. Improvement in diabetic control achieved by increases in insulin dose (mean 1.1 U/kg/day), more frequent insulin doses combined with better dietary control lead to normalization of AP halflife and metabolism, (t½ halflife): All three urinary metabolites of AP were increased to a similar extent in poorly controlled IDDM: N-dimethyl AP ↑60.5±5%, 4-hydroxy AP ↑54±4%, 3-hydroxymethyl AP ↑68±6%. Separate cytochrome P-450 isoenzymes regulating AP metabolism appear to be stimulated to a similar extent in poorly controlled IDDM. Conclusions: Poorly controlled IDDM leads to increased hepatic drug metabolism affecting all three isoenzymes involved in AP metabolism. These data suggest that improved metabolic control normalizes hepatic drug metabolism in IDDM.