Open AccessLack of correlation between UGT1A1*6, *28 genotypes, and plasma raltegravir concentrations in Japanese HIV‐1‐infected patients
Author(s) -
Takahashi M,
Hirano A,
Oishi Y,
Sato M,
Yoshino M,
Ikemura K,
Shibata M,
Fukushima N,
Amioka K,
Nomura T,
Yokomaku Y,
Sugiura W
Publication year - 2012
Publication title -
journal of the international aids society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.724
H-Index - 62
ISSN - 1758-2652
DOI - 10.7448/ias.15.6.18342
Subject(s) - raltegravir , genotyping , genotype , allele , medicine , taqman , glucuronidation , human immunodeficiency virus (hiv) , gastroenterology , biology , virology , genetics , viral load , antiretroviral therapy , polymerase chain reaction , gene , in vitro , microsome
Background Raltegravir is metabolized by glucuronidation via UGT1A1. Among the genetic polymorphisms of UGT1A1, the *6, *27 and *28 alleles are associated with reduced levels of UGT1A1. In particular, the *28 allele accounts for most of the UGT1A1 polymorphisms, and the level of UGT1A1 activity has been the focus of most studies. On the other hand, among Asians, the *6 and *27 alleles are more commonly found in comparison with white populations. In this study, we aimed to clarify the contribution of UGT1A1 polymorphisms (*6, *27) to plasma raltegravir concentrations in Japanese HIV‐1‐infected patients. Materials & Methods We analyzed the presence of genotypic variants (*6, *27 and *28) among the 74 patients recruited at the National Hospital Organization Nagoya Medical Center. Genotyping of *6 and *27 in UGT1A1 was performed using the TaqMan drug metabolism genotyping assay. Genotyping of *28 in UGT1A1 was performed using the primers described by Ehmer et al. Plasma raltegravir concentrations were determined by a LC‐MS method. Results Among the 74 patients, the UGT1A1 genotype in 3 patients (two male, one female) was *6 homozygote. Heterozygous variants were found in 20 patients for *6, and in 14 patients for *28, while all of the patients were found to carry wild‐type sequences at the position corresponding to the *27 allele. The male *6 homozygote patient had modestly higher plasma raltegravir concentration (0.53 µg/ml) than other patients who were wild type (0.12 µg/ml) or heterozygous (0.16 µg/ml) for the *6 polymorphism. The other two UGT1A1*6 homozygote patients had a lower plasma raltegravir concentration (0.03 and 0.05 µg/ml). On the other hand, plasma raltegravir concentrations were 0.12 µg/ml (*6−/− *28−/−; n=37), 0.11 µg/ml (*6−/− *28−/+; n=14), 0.16 µg/ml (*6−/+ *28−/−; n=20). There were no statistically significant differences in the plasma raltegravir concentrations between patients carrying wild‐type alleles and those heterozygous for *6 or *28. Conclusions Patients heterozygous for the *6 or *28 allele did not display significantly different plasma raltegravir concentrations compared to patients homozygous for the respective wild‐type allele. In this study, we showed that heterozygosity for the reduced‐function *6 and *28 alleles had no significant effect on plasma raltegravir concentrations in Japanese HIV‐1‐infected patients.