Lidocaine metabolism in isolated perfused liver from streptozotocin-induced diabetic rats.

Insulin deficiency can trigger not only an altered glucose metabolic state but may also affect drug metabolism. The formation rate of the major lidocaine metabolite monoethylglycinxylidide (MEGX) has been shown to reflect the activity of CYP3A2 and CYP1A2. In the present study the effects of streptozotocin-induced diabetes on lidocaine elimination and MEGX formation in a model of isolated, non-recirculated, perfused rat liver with constant flow was evaluated. The parameters describing hepatic lidocaine elimination studied 10 days after streptozotocin administration, i.e. hepatic extraction coefficient (E(H)), hepatic clearance (Cl(H)) and elimination rate (V(L)), were significantly decreased in diabetic livers in comparison with the controls. The E(H) in the controls varied between 0.88+/-0.07 and 0.93+/-0.06, whereas in diabetic livers it was markedly reduced to between 0.27+/-0.15 and 0.39+/-0.23. The Cl(H) dropped to 8.04+/-4.12 - 11.66+/-2.99 mL min(-1) in diabetic rats in comparison to 26.29+/-2.07 - 27.94+/-0.92 mL min(-1) in the control animals. The V(L) was estimated to be 128.08+/-18.60 - 136.44+/-17.59 microg mL(-1) in the controls and from 40.87+/-28.31 microg mL(-1) to 56.83+/-22.16 microg mL(-1) in diabetic perfused livers. The major lidocaine metabolite, i.e. MEGX, concentrations were significantly decreased in diabetic rats compared to the controls. The observed changes indicate an impairment of N-deethylation metabolic pathway in streptozotocin-induced diabetic rats, i.e. a possible decrease in the enzymatic activity of CYP3A2 and CYP1A2.