Minimal effect of ketoconazole on cyclosporine (SangCYA™) oral absorption and first-pass metabolism in rats:: Evidence of a significant vehicle effect on SangCyA absorption

The current work evaluated the effect of the CYP3A inhibitor ketoconazole on the oral absorption and first-pass metabolism of cyclosporine administered as the SangCyA formulation. Groups of 6 male Sprague-Dawley rats were administered SangCyA (5 and 15 mg/kg) by oral gavage alone and with ketoconazole (30 mg/kg). Blood cyclosporine levels were measured over 6 h, encompassing the cyclosporine absorption window. A significant vehicle effect on SangCyA absorption was observed. Comparing a 15 mg/kg dose, cyclosporine C-max (mean +/- SD 1.12 +/- 0.16 mug/ml) and AUC(0-6) (5.34 +/- 0.71 mug h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.19 +/- 0.94 mug/ml and 9.52 +/- 2.52 mug h/ml, respectively). Coefficients-of-variation for these parameters were halved in the propylene glycol vehicle however T-max was unaffected. Ketoconazole increased cyclosporine C-max and AUC(0-6) by 50-60%, regardless of the vehicle or the cyclosporine dose, without altering T-max (2-3h). The small effect of ketoconazole suggests that CYP3A-mediated intestinal and first-pass hepatic metabolism are minor determinants of cyclosporine oral bioavailability in rats. Copyright (C) 2002 John Wiley Sons, Ltd.