Balandraud-Pieri N, Queneau P E, Caroli-Bosc F X, Bertault-Pérès P, Montet A M, Durand A, Montet J C
INSERM, Laboratoire de Physiopathologie Hépatique, Marseille, France.
Drug Metab Dispos. 1997 Aug;25(8):912-6.
Cyclosporin A (CsA) exhibits poor bioavailability after oral administration of Sandimmune, with wide intra- and interindividual variations. Our study sought to determine the effect of the coadministration of CsA standard oily formulation and tauroursodeoxycholate (TUDC) and that of an aqueous micellar solution containing TUDC, monoolein, and CsA in promoting and regulating CsA bioavailability in the rat Pharmacokinetic parameters of CsA were determined in fasted rats after either an intravenous administration (5 mg/kg) or a single oral CsA dose of 10 mg/kg. Compared with oral Sandimmune, the CsA micellar solution significantly improved the CsA bioavailability by 160% and decreased the interindividual variability in bioavailability expressed as percent coefficient of variation from 32% to 15%. The concentration-time profile was modified with a 3.5-fold increase in C(max), a reduction of t(max), and an increased trough concentration. Bioavailability slightly improved in rats receiving standard oily solution plus concomitant TUDC, although not significantly. Data indicate that the structure of the CsA carriers greatly affect drug bioavailability and that aqueous micellar solutions of CsA-TUDC-monoolein constitute efficient vehicles, thus providing for CsA high absorption with low variability.
口服山地明后，环孢素A（CsA）的生物利用度较差，个体内和个体间差异较大。我们的研究旨在确定CsA标准油性制剂与牛磺熊去氧胆酸（TUDC）联合给药以及含有TUDC、单油酸甘油酯和CsA的胶束水溶液在促进和调节大鼠体内CsA生物利用度方面的作用。在禁食大鼠中，静脉注射（5mg/kg）或单次口服10mg/kg的CsA后，测定CsA的药代动力学参数。与口服山地明相比，CsA胶束溶液显著提高了CsA的生物利用度，提高了160%，并将以变异系数百分比表示的生物利用度个体间变异性从32%降至15%。浓度-时间曲线发生改变，C(max)增加3.5倍，t(max)降低，谷浓度增加。接受标准油性溶液加同时给予TUDC的大鼠生物利用度略有改善，尽管不显著。数据表明，CsA载体的结构极大地影响药物生物利用度，CsA-TUDC-单油酸甘油酯的胶束水溶液构成了有效的载体，从而使CsA具有高吸收和低变异性。
