Effects of the CYP2C9*13 allele on the pharmacokinetics of losartan in healthy male subjects

Abstract

1. The aim of the study was to determine the pharmacokinetics of losartan in relation to the CYP2C9*13 allele.

2. A single oral dose of 50 mg losartan was administrated to each of the 16 healthy male volunteers with a different genotype (CYP2C9*1/*1, n = 6; CYP2C9*1/*13, n = 4; and CYP2C9*1/*3, n = 6). Blood samples were collected from pre-dose up to 24 h after the drug administration. Plasma losartan and E3174 (an active metabolite of losartan) were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

3. All the subjects finished the study without adverse drug effects. In the present study, the frequencies of CYP2C9*13 and *13 alleles were 0.6% and 2.6% in Chinese healthy volunteers, respectively, and both alleles were in Hardy–Weinberg equilibrium. Compared with the subjects in the CYP2C9*1/*1 group, individuals carrying the CYP2C9*1/*13 genotype showed significantly a longer t_1/2 of losartan and E3174 and markedly increased the area under the curve (AUC) of losartan. Meanwhile, the CYP2C9*1/*3 genotype group had significant differences in t_1/2 and C_max of E3174 compared with the CYP2C9*1/*1 group. The ratio of AUC_E3174/AUC_losartan after losartan administration in the CYP2C9*1/*13 and CYP2C9*1/*3 groups was also statistically different from that in the CYP2C9*1/*1 group.

4. The data indicate that the presence of the CYP2C9*13 allele results in poor metabolism of losartan after a single oral dose.

Keywords::

• CYP2C9
• polymorphism
• lorartan
• E3174
• pharmacokinetics

Acknowledgements

This work was supported by research grants from the National Natural Science Foundation of China (Grant Numbers 30000211, 30200346, and 30472054), by the China Medical Board of New York (Grant Number 01-755), and by the Postdoctoral Science Foundation of Central South University.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.