a Department of Microbiology and Immunology , KU Leuven - University of Leuven , Leuven , Belgium ;
b Department of Nephrology and Renal Transplantation , University Hospitals Leuven , Leuven , Belgium ;
Drug Metab Rev. 2016;48(1):88-112. doi: 10.3109/03602532.2016.1151037. Epub 2016 Feb 25.
The calcineurin inhibitors (CNIs) tacrolimus and cyclosporine are widely used immunosuppressive drugs characterized by high pharmacokinetic and pharmacodynamic variability, both between and within patients. CNIs are highly lipophilic, poorly soluble, undergo extensive first-pass metabolism and are cleared by the liver. In both gut and liver, CNIs are substrates for the cytochrome P450 (CYP) enzymes 3A4 and 3A5 as well as the P-glycoprotein (P-gp) transporter, whose functions are determined by a complex interplay between genetic polymorphisms, the inductive or inhibitory effects of many drugs, herbs, food constituents and endogenous substances such as uremic toxins in case of end-stage renal disease. The current literature is reviewed for all common clinical determinants of variability in CNI disposition such as food intake, diarrhea and other intestinal pathology, anemia, hypoalbuminemia, hyperlipidemia, liver and kidney disease, aging, ethnicity, formulation and time post-transplant, focusing on the underlying mechanisms. Drugs and herb- and food constituents mainly interact with CNIs at the gut level by affecting bioavailability, with interactions generally being much more pronounced in case of oral compared with intravenous co-administration. Cyclosporine disposition is less susceptible to these interactions compared with tacrolimus, possibly because cyclosporine is itself a moderately strong CYP3A4- and strong P-gp inhibitor, blunting the effect of additional inhibitors. P-gp also has a major role in limiting distribution of CNI to tissues such as the brain, placenta, lymphocytes and kidney. Inactivating polymorphisms and inhibition of P-gp have the potential to significantly increase CNI exposure in these tissues with possible implications for toxicity and efficacy.
钙调磷酸酶抑制剂（CNI）他克莫司和环孢素是广泛使用的免疫抑制剂，其药代动力学和药效动力学具有高度变异性，无论是在患者之间还是在患者内部。CNI 具有高亲脂性、低溶解度、广泛的首过代谢和肝脏清除。在肠道和肝脏中，CNI 是细胞色素 P450（CYP）酶 3A4 和 3A5 以及 P-糖蛋白（P-gp）转运体的底物，其功能由遗传多态性、许多药物、草药、食物成分和内源性物质（如终末期肾病的尿毒症毒素）的诱导或抑制作用之间的复杂相互作用决定。本文综述了 CNI 处置变异性的所有常见临床决定因素，如食物摄入、腹泻和其他肠道病理学、贫血、低白蛋白血症、高脂血症、肝和肾疾病、衰老、种族、移植后时间和制剂，重点介绍了潜在的机制。药物、草药和食物成分主要通过影响生物利用度在肠道水平与 CNI 相互作用，与口服相比，静脉共同给药时相互作用通常更为明显。与他克莫司相比，环孢素的处置不太容易受到这些相互作用的影响，这可能是因为环孢素本身就是一种中度强的 CYP3A4 和强 P-gp 抑制剂，削弱了其他抑制剂的作用。P-gp 还在限制 CNI 分布到组织（如脑、胎盘、淋巴细胞和肾脏）方面发挥主要作用。失活多态性和 P-gp 抑制有可能显著增加这些组织中的 CNI 暴露，可能对毒性和疗效有影响。
