Ogata M, Uchimura T, Iizuka Y, Murata R, Suzuki S, Toyota T, Hikichi N
Department of Pharmaceutics, Tohoku College of Pharmacy, Sendai, Japan.
Biol Pharm Bull. 1997 Sep;20(9):1026-9. doi: 10.1248/bpb.20.1026.
We previously reported that the pharmacokinetics of cyclosporin A (CyA), particularly absorption, were altered in diabetic rats treated with streptozotocin. In the present study, the effect of diabetes on pharmacokinetics of CyA after intravenous and oral administration of CyA using the blood and lymph and the gastrointestinal transit were examined in Goto-Kakizaki (GK) rats, a genetic model of non-obese non-insulin-dependent diabetes mellitus (NIDDM), and compared to non-diabetic Wistar rats. Although the systemic and lymphatic availability after intravenous administration of CyA to the GK rats was not significantly different from those of the control Wistar rats, those availability after oral administration of CyA to GK rats was markedly reduced in comparison. These results suggest that the pharmacokinetics of CyA, particularly absorption, was altered in GK rats. Studies on the gastrointestinal transit in GK rats showed that the gastric emptying rate was lower than that of Wistar rats, suggesting that a change in gastrointestinal transit in GK rats may influence the absorption of CyA. The gastric emptying rate in GK rats altered not only the systemic availability but also the lymphatic availability, suggesting that the altered systemic availability may cause adverse effects and that altered lymphatic availability may influence the immunosuppressive effects.
我们之前报道过，用链脲佐菌素治疗的糖尿病大鼠中环孢素A（CyA）的药代动力学，尤其是吸收情况，发生了改变。在本研究中，我们在非肥胖非胰岛素依赖型糖尿病（NIDDM）的遗传模型Goto-Kakizaki（GK）大鼠中，研究了糖尿病对静脉注射和口服CyA后的药代动力学的影响，利用血液、淋巴液以及胃肠转运情况进行检测，并与非糖尿病的Wistar大鼠进行比较。虽然给GK大鼠静脉注射CyA后的全身和淋巴利用率与对照Wistar大鼠相比无显著差异，但给GK大鼠口服CyA后的利用率相比明显降低。这些结果表明，GK大鼠中CyA的药代动力学，尤其是吸收情况发生了改变。对GK大鼠胃肠转运的研究表明，其胃排空率低于Wistar大鼠，这表明GK大鼠胃肠转运的变化可能会影响CyA的吸收。GK大鼠的胃排空率不仅改变了全身利用率，还改变了淋巴利用率，这表明全身利用率的改变可能会导致不良反应，而淋巴利用率的改变可能会影响免疫抑制作用。
