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Effect of non-insulin dependent diabetes on cyclosporin A disposition in Goto-Kakizaki (GK) rats.

We previously reported that the pharmacokinetics of cyclosporin A (CyA), particularly absorption, were altered in diabetic rats treated with streptozotocin. In the present study, the effect of diabetes on pharmacokinetics of CyA after intravenous and oral administration of CyA using the blood and lymph and the gastrointestinal transit were examined in Goto-Kakizaki (GK) rats, a genetic model of non-obese non-insulin-dependent diabetes mellitus (NIDDM), and compared to non-diabetic Wistar rats. Although the systemic and lymphatic availability after intravenous administration of CyA to the GK rats was not significantly different from those of the control Wistar rats, those availability after oral administration of CyA to GK rats was markedly reduced in comparison. These results suggest that the pharmacokinetics of CyA, particularly absorption, was altered in GK rats. Studies on the gastrointestinal transit in GK rats showed that the gastric emptying rate was lower than that of Wistar rats, suggesting that a change in gastrointestinal transit in GK rats may influence the absorption of CyA. The gastric emptying rate in GK rats altered not only the systemic availability but also the lymphatic availability, suggesting that the altered systemic availability may cause adverse effects and that altered lymphatic availability may influence the immunosuppressive effects.