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 microg/ml) and AUC(0-6) (5.34+/-0.71 microg h/ml) were 50% lower when propylene glycol was used as gavage vehicle instead of saline (2.19+/-0.94 microg/ml and 9.52+/-2.52 microg 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.
Wong
Susan
S
AvMax Inc., South San Francisco, CA 94080, USA.
Wong
Harrison T
HT
Wacher
Vincent J
VJ
D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004347:Drug Interactions; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects*; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D014677:Pharmaceutical Vehicles; D051381:Rats; D013056:Spectrophotometry, Ultraviolet
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D014677:Pharmaceutical Vehicles; D016572:Cyclosporine; D007654:Ketoconazole