Comparison of bioavailability and metabolism with two commercial formulations of cyclosporine A in rats

Abstract

The bioavailability and metabolism of cyclosporine A (CsA) capsules were compared with two bioequivalent (Food and Drug Administration approved) preparations in rats. Two groups of Wistar-Kyoto rats were given 10 mg/kg q.d. of Sandimmun Neoral (NEO), Novartis Pharma, and CsA (United States Pharmacopeia modified), Eon Labs (EON), as capsules dissolved in water by oral gavage. After reaching steady-state (SS), rats were euthanized 2, 4, 8, 12, and 24 h after dosing. Parallel to this investigation, a single dose (SD) study was also performed. CsA and CsA metabolite concentrations of AM1, AM4N, AM9 were determined by high-performance liquid chromatography in kidney, whole blood, and urine. The bioavailability of EON was 15% lower [area under the curve (AUC)SS blood CsA, 27.9 ± 3.69 mg · h/l] in the blood and was 40% lower (AUCSS kidney CsA, 136.2 ± 21.2 mg · h/l) in the kidney in contrast to NEO (AUCSS blood CsA, 32.1 ± 4.32 mg · h/l and AUCSS kidney CsA, 220.8 ± 29.5 mg · h/l). In contrast, the plasma AM4N level was significantly elevated in group receiving EON (AUCSS blood AM4N, 4.1 ± 0.42 mg · h/l) compared with the other group treated with NEO (AUCSS blood AM4N, 2.9 ± 0.39 mg · h/l). In the kidneys, no significant differences were observed concerning the AM4N concentrations of NEO (AUCSS kidney AM4N, 11.8 ± 1.87 mg · h/l) versus EON (AUCSS kidney AM4N, 12.1 ± 2.14 mg · h/l), but AM1 was increased (AUCSS kidney AM1, 54.3 ± 11.2 mg · h/l) in comparison to NEO (AUCSS kidney AM1, 20.5 +/- 3.56 mg · h/l). Furthermore, EON produced a larger amount of AM4N in the urine (5.8 ± 0.85 μg/24 h versus 2.2 ± 0.95 μg/24 h). Similar results were obtained with the SD study. Although the clinical consequences of our results remain at present unknown, the data suggest differences in CsA disposition that may affect drug efficacy and safety and merit further investigation in humans.