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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
Author(s) -
Wong Susan,
Wong Harrison T.,
Wacher Vincent J.
Publication year - 2002
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.295
Subject(s) - ketoconazole , bioavailability , pharmacokinetics , absorption (acoustics) , cyp3a , first pass effect , pharmacology , chemistry , oral administration , metabolism , endocrinology , medicine , cytochrome p450 , biochemistry , antifungal , physics , dermatology , acoustics
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.