Effects of clarithromycin on the pharmacokinetics of tacrolimus and expression of CYP3A4 and P‐glycoprotein in rats

作者：Jinhua Wen, ChenYang, Menghua Zhao, Weiqiang Hu, Yu Wei Xiao · 发表于：Fundamental and Clinical Pharmacology · 年份：2023 · DOI：10.1111/fcp.12882 · 被引用次数：8 · 研究领域：Renal Transplantation Outcomes and Treatments、Pharmacological Effects and Toxicity Studies、Antibiotics Pharmacokinetics and Efficacy

Abstract The objective of this study was to investigate the effect of clarithromycin on the pharmacokinetics of tacrolimus in rats and better understand its mechanism. In the control group ( n = 6), rats received a single oral dose of 1 mg tacrolimus on day 6. In the experimental group ( n = 6), rats received 0.25 g of clarithromycin daily for five consecutive days and then a single oral dose of 1 mg tacrolimus on day 6. Orbital venous blood (250 μL) was collected at 0, 0.25, 0.50, 0.75, 1, 2, 4, 8, 12, and 24 h before and after tacrolimus administration. Blood drug concentrations were detected via mass spectrometry. Small intestine and liver tissue samples were collected after rats were euthanized via dislocation, and CYP3A4 and P‐glycoprotein (P‐gp) protein expression was determined using western blotting. Clarithromycin increased the blood tacrolimus concentration and affected its pharmacokinetic properties in rats. Compared with those in the control group, the AUC 0–24 , AUC 0–∞ , AUMC (0– t ) , and AUMC (0–∞) of tacrolimus in the experimental group were significantly increased, whereas the CLz/F was significantly lower ( P < 0.01). Simultaneously, clarithromycin significantly inhibited CYP3A4 and P‐gp expression in the liver and intestine. Protein expression of CYP3A4 and P‐gp in the liver and the intestinal tract was significantly downregulated in the intervention group compared with that in the control group. Clarithromycin significantly inhibited the protein expres...