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

  • Lu Huang
  • Liu Yang
  • Jie Huang
  • Hong-yi Tan
  • Shi-kun Liu
  • Cheng-xian Guo
  • Xiao-cong Zuo
  • Guo-ping YangEmail author
  • Qi PeiEmail author
Original Research Article


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.


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.


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.


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.


Compliance with Ethical Standards


The study was supported by grants from the National Scientific Foundation of China (No. 81302851), International Science & Technology Cooperation Program of China (Grant 2014DFA30900); Health Department Foundation of Hunan Province (132013-028), The New Xiangya Talent Projects of the Third Xiangya Hospital of Central South University (No. JY201616).

Conflict of Interest

All authors have no conflicts of interests to declare.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the Third Xiangya Hospital of Central South University.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Bakheit AH, Abd-Elgalil AA, Mustafa B, Mustafa B, Haque A, Wani TA. Telmisartan. Profiles Drug Subst Excip Relat Methodol. 2015;40:371–429.CrossRefGoogle Scholar
  2. 2.
    Deppe S, Boger RH, Weiss J, Benndorf RA. Telmisartan: a review of its pharmacodynamic and pharmacokinetic properties. Expert Opin Drug Metab Toxicol. 2010;6:863–71.CrossRefGoogle Scholar
  3. 3.
    Nishino A, Kato Y, Igarashi T, Sugiyama Y. Both cMOAT/MRP2 and another unknown transporter(s) are responsible for the biliary excretion of glucuronide conjugate of the nonpeptide angiotensin II antagonist, telmisaltan. Drug Metab Dispos. 2000;28:1146–8.PubMedGoogle Scholar
  4. 4.
    Suzuki H, Sugiyama Y. Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition. Adv Drug Deliv Rev. 2002;54:1311–31.CrossRefGoogle Scholar
  5. 5.
    Ishiguro N, Maeda K, Kishimoto W, et al. Predominant contribution of OATP1B3 to the hepatic uptake of telmisartan, an angiotensin II receptor antagonist, in humans. Drug Metab Dispos. 2006;34:1109–15.CrossRefGoogle Scholar
  6. 6.
    Ishiguro N, Maeda K, Saito A, et al. Establishment of a set of double transfectants coexpressing organic anion transporting polypeptide 1B3 and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide. Drug Metab Dispos. 2008;36:796–805.CrossRefGoogle Scholar
  7. 7.
    Miura M, Satoh S, Inoue K, et al. Telmisartan pharmacokinetics in Japanese renal transplant recipients. Clin Chim Acta. 2009;399:83–7.CrossRefGoogle Scholar
  8. 8.
    Guo X, Chen XP, Cheng ZN, et al. No effect of MDR1 C3435T polymorphism on oral pharmacokinetics of telmisartan in 19 healthy Chinese male subjects. Clin Chem Lab Med. 2009;47:38–43.CrossRefGoogle Scholar
  9. 9.
    Yamada A, Maeda K, Ishiguro N, et al. The impact of pharmacogenetics of metabolic enzymes and transporters on the pharmacokinetics of telmisartan in healthy volunteers. Pharmacogenet Genom. 2011;21:523–30.CrossRefGoogle Scholar
  10. 10.
    Deppe S, Ripperger A, Weiss J, et al. Impact of genetic variability in the ABCG2 gene on ABCG2 expression, function, and interaction with AT1 receptor antagonist telmisartan. Biochem Biophys Res Commun. 2014;443:1211–7.CrossRefGoogle Scholar
  11. 11.
    Stangier J, Schmid J, Turck D, et al. Absorption, metabolism, and excretion of intravenously and orally administered [14C]telmisartan in healthy volunteers. J Clin Pharmacol. 2000;40:1312–22.PubMedGoogle Scholar
  12. 12.
    Stangier J, Su CA, Schondorfer G, et al. Pharmacokinetics and safety of intravenous and oral telmisartan 20 mg and 120 mg in subjects with hepatic impairment compared with healthy volunteers. J Clin Pharmacol. 2000;40:1355–64.PubMedGoogle Scholar
  13. 13.
    Peterkin VC, Bauman JN, Goosen TC, et al. Limited influence of UGT1A1*28 and no effect of UGT2B7*2 polymorphisms on UGT1A1 or UGT2B7 activities and protein expression in human liver microsomes. Br J Clin Pharmacol. 2007;64:458–68.CrossRefGoogle Scholar
  14. 14.
    Ando Y, Saka H, Asai G, et al. UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol. 1998;9:845–7.CrossRefGoogle Scholar
  15. 15.
    Yamamoto N, Takahashi T, Kunikane H, et al. Phase I/II pharmacokinetic and pharmacogenomic study of UGT1A1 polymorphism in elderly patients with advanced non-small cell lung cancer treated with irinotecan. Clin Pharmacol Ther. 2009;85:149–54.CrossRefGoogle Scholar
  16. 16.
    Riedmaier S, Klein K, Hofmann U, et al. UDP-glucuronosyltransferase (UGT) polymorphisms affect atorvastatin lactonization in vitro and in vivo. Clin Pharmacol Ther. 2010;87:65–73.CrossRefGoogle Scholar
  17. 17.
    Stangier J, Su CA, Roth W. Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res. 2000;28:149–67.CrossRefGoogle Scholar
  18. 18.
    Tatami S, Sarashina A, Yamamura N, et al. Population pharmacokinetics of an angiotensin II receptor antagonist, telmisartan, in healthy volunteers and hypertensive patients. Drug Metab Pharmacokinet. 2003;18:203–11.CrossRefGoogle Scholar
  19. 19.
    Tatami S, Yamamura N, Sarashina A, et al. Pharmacokinetic comparison of an angiotensin II receptor antagonist, telmisartan, in Japanese and western hypertensive patients using population pharmacokinetic method. Drug Metab Pharmacokinet. 2004;19:15–23.CrossRefGoogle Scholar
  20. 20.
    Zhang P, Zhang Y, Chen X, et al. Pharmacokinetics of telmisartan in healthy Chinese subjects after oral administration of two dosage levels. Arzneimittelforschung. 2006;56:569–73.PubMedGoogle Scholar
  21. 21.
    Williams PJ, Ette EI. The role of population pharmacokinetics in drug development in light of the Food and Drug Administration’s ‘Guidance for Industry: population pharmacokinetics’. Clin Pharmacokinet. 2000;39:385–95.CrossRefGoogle Scholar
  22. 22.
    Pei Q, Yang L, Tan HY, et al. Effects of genetic variants in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, ORM1 on PK/PD of telmisartan in Chinese patients with mild to moderate essential hypertension. Int J Clin Pharmacol Ther. 2017;55:359.CrossRefGoogle Scholar
  23. 23.
    Shen J, Jiao Z, Li ZD, et al. HPLC determination of telmisartan in human plasma and its application to a pharmacokinetic study. Pharmazie. 2005;60:418–20.PubMedGoogle Scholar
  24. 24.
    Kuang Y, Xiang YX, Guo CX, et al. Population pharmacokinetics study of dexmedetomidine in Chinese adult patients during spinal anesthesia [J]. Int J Clin Pharmacol Ther. 2016;54(3):200–7.CrossRefGoogle Scholar
  25. 25.
    Pei Q, Huang L, Huang J, et al. Influences of CYP2D6(*)10 polymorphisms on the pharmacokinetics of iloperidone and its metabolites in Chinese patients with schizophrenia: a population pharmacokinetic analysis [J]. Acta Pharmacol Sin. 2016;37(11):1499–508.CrossRefGoogle Scholar
  26. 26.
    Zuo XC, Zhang WL, Yuan H, et al. ABCB1 polymorphism and gender affect the pharmacokinetics of amlodipine in Chinese patients with essential hypertension: a population analysis [J]. Drug Metab Pharmacokinet. 2014;29(4):305–11.CrossRefGoogle Scholar
  27. 27.
    Goey AK, Figg WD. UGT genotyping in belinostat dosing [J]. Pharmacol Res. 2016;105:22–7.CrossRefGoogle Scholar
  28. 28.
    Harrell RE, Karim A, Zhang W, et al. Effects of age, sex, and race on the safety and pharmacokinetics of single and multiple doses of azilsartan medoxomil in healthy subjects. Clin Pharmacokinet. 2016;55:595–604.CrossRefGoogle Scholar
  29. 29.
    Wang H, Chen H. Gender difference in the response to valsartan/amlodipine single-pill combination in essential hypertension (China Status II): an observational study. J Renin Angiotensin Aldosterone Syst. 2016;17:1607599553.Google Scholar
  30. 30.
    Merino G, van Herwaarden AE, Wagenaar E, et al. Sex-dependent expression and activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP/ABCG2) in liver [J]. Mol Pharmacol. 2005;67(5):1765–71.CrossRefGoogle Scholar
  31. 31.
    Lee U, Kwon MH, Kang HE. Pharmacokinetic alterations in poloxamer 407-induced hyperlipidemic rats [J]. Xenobiotica. 2019;49(5):611–25.CrossRefGoogle Scholar
  32. 32.
    Khalil HA, Elkhatib M, Belal TS, et al. Hyperlipidemia alters the pharmacokinetics of posaconazole and vincristine upon co-administration in rats [J]. Drugs R D. 2017;17(2):287–96.CrossRefGoogle Scholar
  33. 33.
    Kwon MH, Yoon JN, Baek YJ, et al. Effects of poloxamer 407-induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats [J]. Biopharm Drug Dispos. 2016;37(6):352–65.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pharmacy, The Third Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  2. 2.Reproductive and Genetic Hospital of Citic-XiangyaChangshaPeople’s Republic of China
  3. 3.Department of Pharmacy and Center of Clinical Pharmacology, The Third Xiangya HospitalCentral South UniversityHunanPeople’s Republic of China

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