Effects of UGT1A1 Polymorphism, Gender and Triglyceride on the Pharmacokinetics of Telmisartan in Chinese Patients with Hypertension: A Population Pharmacokinetic Analysis.

Background And Objective: Telmisartan is an angiotensin receptor blocker used for the treatment of hypertension. The effects of gender and uridine diphosphate-glycosytransferase 1A1 (UGT1A1) genetic polymorphisms (rs4124874, rs4148323, and rs6742078) on telmisartan plasma concentration and blood pressure in Chinese patients with hypertension have been reported previously. In this study, we aimed to develop a population pharmacokinetic (PopPK) model to quantify the effects of gender and UGT1A1 polymorphisms on the pharmacokinetics of telmisartan.

Methods: Population pharmacokinetic analyses were performed using data collected prospectively from 58 Chinese patients with mild to moderate essential hypertension (aged 45-72 years; 36 men, 22 women) receiving 80 mg/day telmisartan orally for 4 weeks. Blood samples were collected in heparinized tubes at 0, 0.5, 1, and 6 h on day 28 after telmisartan administration. The plasma concentrations and UGT1A1 genetic variants were determined by high-performance liquid chromatography-mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, respectively.

Results: A two-compartment pharmacokinetic structural model with first-order elimination and absorption best described the pharmacokinetic characteristics of telmisartan. Gender and triglyceride influenced the apparent oral clearance (CL) of telmisartan. UGT1A1 (rs4124874) affected the bioavailability (F1) of telmisartan. Lower CL and bioavailability resulted in higher plasma concentrations being observed in female subjects with UGT1A1 CC or CA genotype and high triglyceride.

Conclusion: A PopPK model of telmisartan was established to confirm that UGT1A1 genotype, gender and triglyceride can affect the pharmacokinetics of telmisartan in Chinese patients with hypertension. Our findings can provide relevant pharmacokinetic parameters for further study of telmisartan.