Effect of probenecid on pharmacokinetics and tolerability of olmesartan in healthy chinese volunteers

Kun-Yan Li, Yu Qiu, Yun Jiang, Chen-Hui Luo, Xiao-Ping Lin, Jing Wang, Nong Yang, Kun-Yan Li, Yu Qiu, Yun Jiang, Chen-Hui Luo, Xiao-Ping Lin, Jing Wang, Nong Yang

Abstract

Background: Olmesartan is an angiotensin II receptor antagonist and is effective and well tolerated in the treatment of arterial hypertension. Probenecid is a well-established hypouricemic agent for the treatment of hyperuricemia and gout.

Objective: The goal of this study was to examine the impact of coadministration of probenecid on the pharmacokinetic parameters and tolerability of olmesartan in healthy volunteers.

Methods: In a randomized, open-label, 2-way crossover study, 12 volunteers received 2 oral treatments (olmesartan alone or olmesartan plus probenecid) separated by 4 days. Blood samples were obtained for a 48-hour pharmacokinetic evaluation after drug administration. Tolerability was assessed by monitoring vital signs and laboratory tests before and after administration of the study drug.

Results: Pharmacokinetic parameters were evaluated in 6 male and 6 female healthy volunteers (mean age, 22 [range, 20-25] years]; weight, 56.0 [range, 51.0-60.0] kg). Probenecid coadministration increased olmesartan Css-av, AUC0→∞, and AUC0-48 by 40%, 50%, and 50%, respectively (P = 0.018, 0.000, 0.000, respectively), but there was no statistical significance for Tmax, t1/2, Css-max, and Css-min between olmesartan plus probenecid and olmesartan alone (P = 0.697, 0.053, 0.521, and 0.734, respectively). No serious adverse event (AE) was reported during the study. The proportion of volunteers with AEs in the olmesartan plus probenecid period (5 of 12 [42%]) was higher than that in the olmesartan-alone period (1 of 12 [8%]). All of the AEs during the olmesartan plus probenecid period were abnormal routine urine test results. The AE in olmesartan-alone period was dizziness. All AEs were classified as mild and considered to be at least possibly related to treatment. All volunteers recovered from the AEs by 2 weeks after the end of the study.

Conclusions: Probenecid increases the exposure speed of olmesartan by increasing the AUC0-48, AUC0→∞, and Css-av. The combined treatment of olmesartan medoxomil with probenecid may increase the occurrence of genitourinary side effects. ClinicalTrials.gov identifier: NCT01907373.

Keywords: olmesartan; pharmacokinetics; probenecid; tolerability.

Figures

Figure
Figure
Log-transformed concentration-time curves after administration of olmesartan alone and olmesartan plus probenecid.

References

    1. Iwanaga T., Sato M., Maeda T. Concentration-dependent mode of interaction of angiotensin ii receptor blockers with uric acid transporter. J Pharmacol Exp Ther. 2007;320:211–217.
    1. Silverman W., Locovei S., Dahl G. Probenecid, a gout remedy, inhibits pannexin 1 channels. Am J Physiol Cell Physiol. 2008;295:C761–C767.
    1. Shin H.J., Takeda M., Enomoto A. Interactions of urate transporter URAT1 in human kidney with uricosuric drugs. Nephrology (Carlton) 2011;16:156–162.
    1. Enomoto A., Endou H. Roles of organic anion transporters (OATs) and a urate transporter (URAT1) in the pathophysiology of human disease. Clin Exp Nephrol. 2005;9:195–205.
    1. Unger T., McInnes G.T., Neutel J.M. The role of olmesartan medoxomil in the management of hypertension. Drugs. 2004;64:2731–2739.
    1. Yamada A., Maeda K., Kamiyama E. Multiple human isoforms of drug transporters contribute to the hepatic and renal transport of olmesartan, a selective antagonist of the angiotensin II AT1-receptor. Drug Metab Dispos. 2007;35:2166–2176.
    1. Laeis P., Puchler K., Kirch W. The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction. J Hypertens. 2001;19:S21–S32.
    1. Nakagomi-Hagihara R., Nakai D., Kawai K. OATP1B1, OATP1B3 and MRP2 are involved in hepatobiliary transport of olmesartan, a novel angiotensin II blocker. Drug Metab Dispos. 2006;34:862–869.
    1. World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects: Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the 29th WMA General Assembly, Tokyo, Japan, October 1975; the 35th WMA General Assembly, Venice, Italy, October 1983; the 41st WMA General Assembly, Hong Kong, September 1989; the 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996; the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000; and the 59th WMA General Assembly, Seoul, October 2008.
    1. European Medicines Agency. ICH Topic E 6 (R1) Guideline for Good Clinical Practice (CPMP/ICH/135/95). . Accessed July 13, 2009.
    1. China Food and Drug Administration. The Technical Guideline for Chemical Drug Clinical Pharmacokinetic Study (.(H) GCL1-2 ). March 2005. (in Chinese). Accessed July 13, 2009.
    1. Daiichi Sankyo Pharmaceutical (Shanghai) Co.,Ltd. The instructions of Aotan®. . Accessed October 21, 2009.
    1. Brunner H.R. The new oral angiotensin II antagonist olmesartan medoxomil: a concise overview. J Hum Hypertens. 2002;16:S13–S16.
    1. Li K.Y., Liang J.P., Hu B.Q. The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20-mg capsules and tablets in healthy Chinese male volunteers: an open-label, randomized-sequence, single-dose, three-way crossover study. Clin Ther. 2010;32:1674–1680.
    1. Yoshihara K., Gao Y., Shiga H. Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients. Clin Pharmacokinet. 2005;44:1329–1342.
    1. Schwocho L.R., Masonson H.N. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol. 2001;41:515–527.
    1. Brousil J.A., Burke J.M. Olmesartan medoxomil: an angiotensin II-receptor blocker. Clin Ther. 2003;25:1041–1055.
    1. Olmesartan side effects. . Accessed July 16, 2013.
    1. Probenecid side effects. . Accessed July 16, 2013.

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