Roby K A, Shaw L M
Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia.
J Am Soc Nephrol. 1993 Aug;4(2):168-77. doi: 10.1681/ASN.V42168.
The isolated perfused rat kidney (IPK) was used to study the acute effects of cyclosporin A (CsA) and its metabolites (M1, M17, M18, M21 and M-COOH). GFR, renal vascular resistance, and sodium, potassium and water reabsorption were measured before and after the addition of CsA/metabolites/vehicles. There was no difference in CsA effect (mild decrease in GFR and increase in renal vascular resistance with the inclusion of plasma (10 mL) or whole blood (20 mL) in the albumin perfusate (120 mL). Intralipid was used as the vehicle for CsA and the metabolites because methanol, ethanol, and Cremophor had significant effects on GFR. Intralipid enhanced the effect of CsA 25-fold, giving CsA dose responses comparable to those of human kidneys. This enhanced effect with intralipid was due to vasoconstriction, not vascular obstruction, and was apparently specific to CsA (no enhancement of norepinephrine with Intralipid). The primary metabolites (M1, M17, and M21) caused decreases in GFR comparable to or slightly less than those caused by CsA. The secondary metabolites (M18 and M-COOH) caused more modest declines in GFR. Cyclosporine metabolite levels in patient blood often greatly exceed levels of the parent drug; these studies suggest that the metabolites may contribute significantly to CsA nephrotoxicity in patients.
采用离体灌注大鼠肾脏（IPK）研究环孢素A（CsA）及其代谢产物（M1、M17、M18、M21和M-COOH）的急性效应。在添加CsA/代谢产物/赋形剂前后，测量肾小球滤过率（GFR）、肾血管阻力以及钠、钾和水的重吸收。在白蛋白灌注液（120 mL）中加入血浆（10 mL）或全血（20 mL）时，CsA的效应无差异（GFR轻度降低，肾血管阻力增加）。由于甲醇、乙醇和聚氧乙烯蓖麻油对GFR有显著影响，因此使用脂质乳剂作为CsA及其代谢产物的赋形剂。脂质乳剂使CsA的效应增强了25倍，使CsA的剂量反应与人肾相当。脂质乳剂的这种增强效应是由于血管收缩而非血管阻塞，且显然对CsA具有特异性（脂质乳剂不会增强去甲肾上腺素的作用）。主要代谢产物（M1、M17和M21）导致GFR降低的程度与CsA相当或略低于CsA。次要代谢产物（M18和M-COOH）导致GFR下降幅度较小。患者血液中环孢素代谢产物水平常常大大超过母体药物水平；这些研究表明，代谢产物可能在很大程度上导致患者出现CsA肾毒性。
