环孢素A两种市售制剂在大鼠体内的生物利用度和代谢比较。

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

作者信息

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

机构信息

Department of Pharmacology and Clinical Pharmacology, University of Regensburg, Regensburg, Germany.

出版信息

Drug Metab Dispos. 2002 Jun;30(6):658-62. doi: 10.1124/dmd.30.6.658.

DOI:10.1124/dmd.30.6.658

PMID:12019192

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, 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 mcirog/24 h versus 2.2 +/- 0.95 microg/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.

摘要

在大鼠中，将环孢素A（CsA）胶囊的生物利用度和代谢情况与两种生物等效制剂（美国食品药品监督管理局批准）进行了比较。将两组Wistar-Kyoto大鼠每日经口灌胃给予10mg/kg的新山地明（NEO，诺华制药公司生产）和CsA（美国药典修订版，伊奥制药公司生产，EON），药物以胶囊形式溶于水中。达到稳态（SS）后，在给药后2、4、8、12和24小时对大鼠实施安乐死。与该研究并行，还进行了单剂量（SD）研究。通过高效液相色谱法测定肾脏、全血和尿液中环孢素A及其代谢物AM1、AM4N和AM9的浓度。与NEO相比，EON在血液中的生物利用度降低了15%[曲线下面积（AUC）（稳态血中环孢素A），27.9±3.69mg·h/l]，在肾脏中降低了40%（AUC（稳态肾中环孢素A），136.2±21.2mg·h/l），而NEO的AUC（稳态血中环孢素A）为32.1±4.32mg·h/l，AUC（稳态肾中环孢素A）为220.8±29.5mg·h/l。相比之下，接受EON治疗的组血浆AM4N水平显著升高（AUC（稳态血中AM4N），4.1±0.42mg·h/l），而另一组接受NEO治疗的组为AUC（稳态血中AM4N），2.9±0.39mg·h/l。在肾脏中，NEO的AM4N浓度（AUC（稳态肾中AM4N），11.8±1.87mg·h/l）与EON的（AUC（稳态肾中AM4N），12.1±2.14mg·h/l）相比，未观察到显著差异，但与NEO（AUC（稳态肾中AM1），20.5±3.56mg·h/l）相比，EON的AM1增加（AUC（稳态肾中AM1），54.3±11.2mg·h/l）。此外，EON在尿液中产生的AM4N量更大（5.8±0.85μg/24小时，而NEO为2.2±0.95μg/24小时）。单剂量研究也得到了类似结果。尽管目前我们的研究结果的临床后果尚不清楚，但数据表明环孢素A处置存在差异，这可能会影响药物疗效和安全性，值得在人体中进一步研究。