Vol. 30, Issue 6, 658-662, June 2002

Comparison of Bioavailability and Metabolism with Two Commercial Formulations of Cyclosporine A in Rats

Jens Koehler, Thomas Kuehnel, Frieder Kees, Klaus Hoecherl, and Horst F. Grobecker

Department of Pharmacology and Clinical Pharmacology, University of Regensburg (J.K., F.K., K.H., H.F.G.); and Clinic of Head and Neck Surgery, University Hospital Regensburg (T.K.), Regensburg, Germany

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, and 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 (AUC_{SS kidney CsA}, 136.2 ± 21.2 mg · h/l) in the kidney in contrast to NEO (AUC_{SS blood CsA}, 32.1 ± 4.32 mg · h/l and AUC_{SS kidney CsA}, 220.8 ± 29.5 mg · h/l). In contrast, the plasma AM4N level was significantly elevated in group receiving EON (AUC_{SS blood AM4N}, 4.1 ± 0.42 mg · h/l) compared with the other group treated with NEO (AUC_{SS blood AM4N}, 2.9 ± 0.39 mg · h/l). In the kidneys, no significant differences were observed concerning the AM4N concentrations of NEO (AUC_{SS kidney AM4N}, 11.8 ± 1.87 mg · h/l) versus EON (AUC_{SS kidney AM4N}, 12.1 ± 2.14 mg · h/l), but AM1 was increased (AUC_{SS kidney AM1}, 54.3 ± 11.2 mg · h/l) in comparison to NEO (AUC_{SS 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.