Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Oslo, Norway.
Department of Nephrology, Akershus University Hospital, Lørenskog, Norway.
Clin Pharmacol Ther. 2020 Oct;108(4):866-873. doi: 10.1002/cpt.1875. Epub 2020 Jun 1.
Drug dosing is challenging in patients with end-stage renal disease. Not only is renal drug elimination reduced, but nonrenal clearance pathways are also altered. Increasing evidence suggest that uremia impacts drug metabolizing enzymes and transporters leading to changes in nonrenal clearance. However, the exact mechanisms are not yet fully understood, and the acute effects of dialysis are inadequately investigated. We prospectively phenotyped cytochrome P450 3A (CYP3A; midazolam) and P-glycoprotein (P-gp)/organic anion-transporting proteins (OATP; fexofenadine) in 12 patients on chronic intermittent hemodialysis; a day after ("clean") and a day prior to ("dirty") dialysis. Unbound midazolam clearance decreased with time after dialysis; median (range) reduction of 14% (-3% to 41%) from "clean" to "dirty" day (P = 0.001). Fexofenadine clearance was not affected by time after dialysis (P = 0.68). In conclusion, changes in uremic milieu between dialysis sessions induce a small, direct inhibitory effect on CYP3A activity, but do not alter P-gp/OATP activity.
在终末期肾病患者中，药物剂量调整颇具挑战。不仅肾脏清除药物的能力降低，非肾脏清除途径也发生改变。越来越多的证据表明，尿毒症会影响药物代谢酶和转运体，导致非肾脏清除的变化。然而，确切的机制尚未完全阐明，透析的急性效应也研究不足。我们前瞻性地对 12 名接受慢性间歇性血液透析的患者进行了细胞色素 P450 3A（CYP3A；咪达唑仑）和 P-糖蛋白（P-gp）/有机阴离子转运蛋白（OATP；非索非那定）表型分析；分别在透析后“干净”日（“clean” day）和前“脏”日（“dirty” day）一天后进行。未结合咪达唑仑清除率随透析后时间而降低；与“干净”日相比，“脏”日时下降 14%（-3%至 41%）（P=0.001）。非索非那定清除率不受透析后时间影响（P=0.68）。总之，透析间隙中尿毒症环境的变化会对 CYP3A 活性产生轻微的直接抑制作用，但不会改变 P-gp/OATP 活性。
