Altered liver function in diabetes: model experiments with aminopyrine in the rat

The aminopyrine breath test is a valuable quantitative liver function test. However, it may be influenced by factors not related primarily to liver disease. For instance, it has been published that diabetes affects microsomal demethylation of aminopyrine in vitro. The relevance of these findings for the in vivo situation, however, is ill defined. Aminopyrine disposition was evaluated, therefore, by performing an in vivo-in vitro comparison of its kinetics in control, diabetic and insulin-treated diabetic rats. Diabetes was induced by streptozotocin (75 mg/kg i.v.). A tracer dose of [14C]aminopyrine was injected i.p. (40 mu Ci/kg, 0.7 mg/kg) and the kinetics of 14CO2 in breath as well as disappearance of aminopyrine in blood were followed simultaneously for 2 hr. Diabetes increased the 14CO2 elimination rate constant in breath by 90%, whereas total recovery of 14CO2 in breath was decreased by 30% (P less than .001). Aminopyrine clearance in blood was doubled in diabetic rats compared to control (48.9 +/- 11.3 vs. 21.4 +/- 3.3 ml/min X kg, P less than .001). This was due to an increased volume of distribution (1.99 +/- 0.31 in diabetic rats vs. 0.96 +/- 0.11 liters/kg in control). In vitro aminopyrine kinetics in hepatic microsomal preparations showed a 52% higher Vmax of aminopyrine demethylase in D (P less than .001), whereas Km remained unchanged. The diabetes-induced changes were reversible by insulin. It is concluded that diabetes alters the aminopyrine breath test by interfering with demethylation rate and distribution of aminopyrine, and by changing the fate of the cleaved C1-fragments.