Minimal effect of ketoconazole on cyclosporine (SangCyA TM ) 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 µg/ml) and AUC 0−6 (5.34±0.71 µg h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.19±0.94 µg/ml and 9.52±2.52 µg 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 (2–3 h). 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 © 2002 John Wiley & Sons, Ltd.