Strong M L, Ueda C T
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, College of Pharmacy, Omaha 68198-6000, USA.
Pharm Res. 1997 Oct;14(10):1466-71. doi: 10.1023/a:1012141309951.
This study investigated the effects of low (LDL) and high density lipoproteins (HDL) on renal cyclosporine A (CsA) and cyclosporine G (CsG) disposition in the isolated perfused rat kidney model.
Kidneys were perfused with CsA or CsG in perfusion medium containing 6% protein, bovine serum albumin only (BSA) (Control), LDL (200 mg/dl) and BSA, or HDL (200 mg/dl) and BSA. In vitro protein binding studies were conducted with CsA and CsG in the same media.
The unbound fractions (fu) of CsA and CsG were significantly reduced with LDL and HDL in the perfusion media. In the presence of LDL, fu for CsA and CsG was 3.9% and 5.9%, respectively. With HDL, fu was 2.1% for CsA and 1.8% for CsG. fu for the controls was 14.7% for CsA and 11.9% for CsG. Renal clearance (CLR) of CsA and CsG was significantly reduced when perfused with perfusion medium containing LDL and HDL. LDL and HDL had similar effects on reducing CsA and CsG CLR, and were approximately four-fold lower when compared to controls (approximately 0.006 Vs. 0.023 ml/min). Renal CsA and CsG tissue (whole organ, cortex and medulla) concentrations were lower than corresponding controls when perfused with LDL or HDL.
The interaction of CsA and CsG with LDL and HDL significantly reduced the CLR and extent of renal tissue distribution of both compounds.
本研究在离体灌注大鼠肾脏模型中，研究了低密度脂蛋白（LDL）和高密度脂蛋白（HDL）对肾环孢素A（CsA）和环孢素G（CsG）处置的影响。
在含有6%蛋白质、仅牛血清白蛋白（BSA）（对照）、LDL（200mg/dl）和BSA或HDL（200mg/dl）和BSA的灌注培养基中，用CsA或CsG灌注肾脏。在相同培养基中对CsA和CsG进行体外蛋白质结合研究。
灌注培养基中加入LDL和HDL后，CsA和CsG的未结合分数（fu）显著降低。在LDL存在下，CsA和CsG的fu分别为3.9%和5.9%。对于HDL，CsA的fu为2.1%，CsG的fu为1.8%。对照的fu，CsA为14.7%，CsG为11.9%。当用含有LDL和HDL的灌注培养基灌注时，CsA和CsG的肾清除率（CLR）显著降低。LDL和HDL对降低CsA和CsG的CLR具有相似的作用，与对照相比降低了约四倍（约0.006对0.023ml/min）。当用LDL或HDL灌注时，肾脏CsA和CsG组织（全器官、皮质和髓质）浓度低于相应对照。
CsA和CsG与LDL和HDL的相互作用显著降低了两种化合物的CLR和肾组织分布范围。
