Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 Leiden, The Netherlands.
Genes (Basel). 2020 Oct 15;11(10):1205. doi: 10.3390/genes11101205.
Tacrolimus-modified release formulations allow for once-daily dosing, and adherence is better compared to the twice-daily immediate release formulation. When patients are switched from one formulation to another, variable changes in drug concentrations are observed. Current data suggest that the changes in drug exposure are larger in patients who express the CYP3A5 enzyme () compared to nonexpressers (). Possibly, these differences are due to the fact that in the upper region of the small intestine CYP3A activity is higher, and that this expression of CYP3A decreases towards the more distal parts of the gut. Modified release formulations may therefore be subject to a less presystemic metabolism. However, the full implications of pharmacogenetic variants affecting the expression and function of drug transporters in the gut wall and of enzymes involved in phase I and phase II metabolism on the different formulations are incompletely understood, and additional studies are required. Conclusions: In all patients in whom the formulation of tacrolimus is changed, drug levels need to be checked to avoid clinically relevant under- or overexposure. In patients with the expresser genotype, this recommendation is even more important, as changes in drug exposure can be expected.
他克莫司缓控释制剂可每日给药 1 次，与每日 2 次的普通速释制剂相比，患者的依从性更好。当患者从一种制剂转换为另一种制剂时，会观察到药物浓度的变化。目前的数据表明，与非表达者（）相比，表达 CYP3A5 酶（）的患者药物暴露的变化更大（）。可能是由于在上段小肠中 CYP3A 的活性更高，而这种 CYP3A 的表达在肠道的更远端部位减少。因此，缓控释制剂可能受到较少的首过代谢影响。然而，影响肠道壁中药物转运体表达和功能以及涉及 I 相和 II 相代谢的酶的药物遗传学变异对不同制剂的全部影响尚不完全清楚，需要进一步研究。结论：在所有改变他克莫司制剂的患者中，需要检查药物水平以避免出现临床相关的药物暴露不足或过量。在具有表达基因型的患者中，这一建议更为重要，因为预计药物暴露会发生变化。
