School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
College of Pharmacy, Dankook University, Cheonan, 31116, Republic of Korea.
Arch Pharm Res. 2021 Dec;44(12):1109-1119. doi: 10.1007/s12272-021-01363-1. Epub 2021 Nov 24.
Candesartan cilexetil is an angiotensin II receptor blocker and it is widely used to treat hypertension and heart failure. This drug is a prodrug that rapidly converts to candesartan after oral administration. Candesartan is metabolized by cytochrome P450 2C9 (CYP2C9) enzyme or uridine diphosphate glucurinosyltransferase 1A3, or excreted in an unchanged form through urine, biliary tract and feces. We investigated the effect of genetic polymorphism of CYP2C9 enzyme on drug pharmacokinetics using physiologically based pharmacokinetic (PBPK) modeling. In addition, by introducing the age and ethnicity into the model, we developed a model that can propose an appropriate dosage regimen taking into account the individual characteristics of each patient. To evaluate the suitability of the model, the results of a clinical trial on twenty-two healthy Korean subjects and their CYP2C9 genetic polymorphism data was applied. In this study, PK-Sim® was used to develop the PBPK model of candesartan.
坎地沙坦西酯是一种血管紧张素 II 受体阻滞剂，广泛用于治疗高血压和心力衰竭。该药是一种前体药物，口服后迅速转化为坎地沙坦。坎地沙坦主要通过细胞色素 P450 2C9（CYP2C9）酶或尿苷二磷酸葡萄糖醛酸转移酶 1A3 代谢，或以原形经尿液、胆道和粪便排泄。我们利用基于生理学的药代动力学（PBPK）模型研究了 CYP2C9 酶遗传多态性对药物药代动力学的影响。此外，通过将年龄和种族引入模型，我们开发了一种能够根据每个患者的个体特征提出适当剂量方案的模型。为了评估模型的适用性，将 22 名健康韩国受试者的临床试验结果及其 CYP2C9 遗传多态性数据应用于该模型。本研究采用 PK-Sim®软件建立坎地沙坦的 PBPK 模型。
