AIDS Reference center, Cliniques Universitaires Saint-Luc, 1200, Brussels, Belgium.
Louvain centre for Toxicology and Applied Pharmacology (LTAP), Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain (UCL), 1200, Brussels, Belgium.
Sci Rep. 2018 May 9;8(1):7359. doi: 10.1038/s41598-018-25803-z.
The aim of this study was to evaluate the effect of UGT1A1 polymorphisms on Raltegravir (RAL) and its metabolite RAL-glucuronide trough plasma concentrations ([RAL]plasma and [RAL-glu]plasma) and on the metabolic ratio (MR): [RAL-glu]plasma/[RAL]plasma. UGT1A1 genotyping was performed on 96 patients. 44% (n = 42) were homozygous UGT1A11/1 while 50% (n = 48) and 6% (n = 6) were UGT1A128 and UGT1A136 carriers, respectively. The median concentration and interquartile range (IQR) of [RAL]plasma were 88.5 ng/ml (41.0-236), 168 ng/ml (85.8-318) and 92.5 ng/ml (36.4-316) for UGT1A11/1, UGT1A128 and UGT1A136 carriers, respectively. Only the difference between UGT1A11/1 and 28 carriers was statistically significant (p = 0.022). The median MR (IQR) were 5.8 (3-10), 2.9 (1.6-5.3) and 3.2 (1.7-5.9) for UGT1A11/1, UGT1A128 and UGT1A136 carriers, respectively. Only the difference between UGT1A11/*1 and 28 carriers was statistically significant (p = 0.004) with an allele-dependent effect: UGT1A128 homozygous having lower MR than heterozygous carriers who show lower MR compared to 1/1. Except for the sensation of fatigue, this PK effect did not correlate with clinical adverse events or biological abnormalities. In Conclusion, we demonstrate that UGT1A128 polymorphism has a significant impact on RAL metabolism: UGT1A128 carriers being characterized by higher [RAL]plasma and lower MR.
本研究旨在评估 UGT1A1 多态性对拉替拉韦（RAL）及其代谢产物 RAL-葡萄糖醛酸苷谷浓度（[RAL]血浆和[RAL-glu]血浆）以及代谢比（MR）：[RAL-glu]血浆/[RAL]血浆的影响。对 96 例患者进行 UGT1A1 基因分型。44%（n=42）为 UGT1A11/1 纯合子，50%（n=48）和 6%（n=6）分别为 UGT1A128 和 UGT1A136 携带者。[RAL]血浆的中位数浓度和四分位间距（IQR）分别为 UGT1A11/1、UGT1A128 和 UGT1A136 携带者的 88.5ng/ml（41.0-236）、168ng/ml（85.8-318）和 92.5ng/ml（36.4-316）。只有 UGT1A11/1 和28 携带者之间的差异具有统计学意义（p=0.022）。MR（IQR）的中位数分别为 UGT1A11/1、UGT1A128 和 UGT1A136 携带者的 5.8（3-10）、2.9（1.6-5.3）和 3.2（1.7-5.9）。只有 UGT1A11/1 和28 携带者之间的差异具有统计学意义（p=0.004），且具有等位基因依赖性效应：UGT1A128 纯合子的 MR 低于杂合子携带者，杂合子携带者的 MR 又低于1/1 纯合子。除疲劳感外，这种药代动力学效应与临床不良事件或生物学异常无关。总之，我们证明 UGT1A128 多态性对 RAL 代谢有显著影响：UGT1A1*28 携带者的[RAL]血浆较高，MR 较低。
