The angiotensin receptor blocker telmisartan slows progression of kidney disease in patients with type 2 diabetes (T2D), yet many patients remain at high risk for progressive kidney function loss. The underlying mechanisms for this response variation might be attributed to differences in angiotensin-1 receptor occupancy (RO), resulting from individual variation in plasma drug exposure, tissue drug exposure, and receptor availability. Therefore, we first assessed the relationship between plasma telmisartan exposure and urinary-albumin-to-creatinine-ratio (UACR) in 10 patients with T2D and albuminuria (mean age 66 years, median UACR 297 mg/g) after 4 weeks treatment with 80 mg telmisartan once daily. Increasing telmisartan exposure associated with a larger reduction in UACR (Pearson correlation coefficient (PCC) = −0.64, P = 0.046, median change UACR: −40.1%, 95% confidence interval (CI): −22.9 to −77.4%, mean telmisartan area under the curve (AUC) = 2927.1 ng·hour/mL, 95% CI: 723.0 to 6501.6 ng·hour/mL). Subsequently, we assessed the relation among plasma telmisartan exposure, kidney distribution, and angiotensin-1 RO in five patients with T2D (mean age 60 years, median UACR 72 mg/g) in a separate positron emission tomography imaging study with [¹¹C]Telmisartan. Individual plasma telmisartan exposure correlated with telmisartan distribution to the kidneys (PCC = 0.976, P = 0.024). A meaningful RO could be calculated in three patients receiving 120 mg oral telmisartan, and although high exposure seems related to higher RO, with AUC_0–last of 31, 840, and 274 ng·hour/mL and corresponding RO values 5.5%, 44%, and 59%, this was not significant (P = 0.64). Together these results indicate, for the first time, a relationship among interindividual differences in plasma exposure, kidney tissue distribution, RO, and ultimately UACR response after telmisartan administration.

中文翻译：

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使用 [11C] 替米沙坦研究 2 型糖尿病患者的替米沙坦血浆暴露、肾脏分布、受体占据和反应

血管紧张素受体阻滞剂替米沙坦可减缓 2 型糖尿病 (T2D) 患者肾脏疾病的进展，但许多患者仍处于进行性肾功能丧失的高风险中。这种反应变化的潜在机制可能归因于血管紧张素-1 受体占有率 (RO) 的差异，这是由血浆药物暴露、组织药物暴露和受体可用性的个体差异引起的。因此，我们首先评估了 10 名患有白蛋白尿的 T2D 患者（平均年龄 66 岁，中位 UACR 297 mg/g）在使用 80毫克替米沙坦，每日一次。增加替米沙坦暴露与 UACR 的更大降低相关（皮尔逊相关系数 (PCC) = −0.64，P = 0.046，中位变化 UACR：-40.1%，95% 置信区间 (CI)：-22.9 至 -77.4%，平均替米沙坦曲线下面积 (AUC) = 2927.1 ng·小时/mL，95% CI：723.0 至 6501.6纳克·小时/毫升）。随后，我们在一项单独的正电子发射断层扫描成像研究中评估了五名 T2D 患者（平均年龄 60 岁，中位 UACR 72 mg/g）的血浆替米沙坦暴露、肾脏分布和血管紧张素-1 RO 之间的关系 [ ¹¹ C]替米沙坦。个体血浆替米沙坦暴露与替米沙坦在肾脏的分布相关（PCC = 0.976，P  = 0.024）。在接受 120 mg 口服替米沙坦的三名患者中可以计算出有意义的 RO，尽管高暴露似乎与较高的 RO 相关，但 AUC_{为 0–last}31、840 和 274 ng·hour/mL 以及相应的 RO 值分别为 5.5%、44% 和 59%，这并不显着（P  = 0.64）。这些结果共同表明，替米沙坦给药后血浆暴露、肾组织分布、RO 和最终 UACR 反应的个体差异之间存在关联。