Croatian Agency for Medicinal Products and Medical Devices, Zagreb, Croatia.
University Hospital Centre Zagreb, Analytical Toxicology and Pharmacology Division, Department of Laboratory Diagnostics, Zagreb, Croatia.
Br J Clin Pharmacol. 2018 Sep;84(9):2106-2119. doi: 10.1111/bcp.13646. Epub 2018 Jul 8.
To investigate the impact of glucuronidation enzyme (UGT1A43 142T>G, UGT1A42 70C>A, UGT2B7 -161C>T) and transporter (MDR1/ABCB1 1236C>T, ABCG2 421C>A) polymorphisms on steady-state disposition of lamotrigine and on the lamotrigine-valproate interaction.
Adults with epilepsy on lamotrigine monotherapy (n = 131) or lamotrigine + valproate treatment (n = 74) were genotyped and steady-state lamotrigine and valproate morning troughs were determined as a part of routine therapeutic drug monitoring.
No effect of UGT and MDR1/ABCB1 polymorphisms was observed. In the entire cohort, ABCG2 421A allele had no effect however an interaction between the variant allele and valproate was observed: (i) in lamotrigine-only patients, variant allele (vs. wild type homozygosity) was independently (adjustments: age, sex, body mass index, lamotrigine dose, other polymorphisms) associated with mildly lower lamotrigine troughs [geometric means ratio (GMR) = 0.76, 95% confidence interval (CI) 0.59-0.98], whereas in lamotrigine + valproate patients it was associated with higher troughs (GMR = 1.72, 95%CI 1.14-2.62); (ii) valproate cotreatment was overall associated with markedly higher troughs vs. lamotrigine monotherapy (GMR = 3.49, 95%CI 2.73-4.44), but more so in variant allele carriers (GMR = 5.24, 95%CI 3.38-8.15) than in wild type homozygotes (GMR = 2.32, 95%CI 1.89-2.83); (iii) variant allele effects in two treatment subsets and valproate effects in two genotype subsets differed by 2.36-fold (95%CI 1.39-3.67); (iv) increase in lamotrigine troughs associated with increasing valproate troughs was greater in variant allele carriers than in wild type homozygotes, i.e. variant allele effect increased with increasing valproate troughs.
This study is first to indicate a potentially relevant interaction between ABCG2 421C>A polymorphism and valproate in their effects on lamotrigine disposition.
研究葡萄糖醛酸转移酶（UGT1A43 142T>G、UGT1A42 70C>A、UGT2B7-161C>T）和转运蛋白（MDR1/ABCB1 1236C>T、ABCG2 421C>A）多态性对拉莫三嗪稳态分布的影响，以及对拉莫三嗪-丙戊酸相互作用的影响。
对接受拉莫三嗪单药治疗（n=131）或拉莫三嗪+丙戊酸治疗（n=74）的癫痫成人患者进行基因分型，并作为常规治疗药物监测的一部分，测定稳态拉莫三嗪和丙戊酸的清晨谷浓度。
未观察到 UGT 和 MDR1/ABCB1 多态性的影响。在整个队列中，ABCG2 421A 等位基因没有影响，但观察到该变异等位基因与丙戊酸之间存在相互作用：（i）在仅接受拉莫三嗪治疗的患者中，与野生型纯合子相比，变异等位基因（vs. 野生型纯合子）独立（调整因素：年龄、性别、体重指数、拉莫三嗪剂量、其他多态性）与拉莫三嗪谷浓度略有降低相关[几何均数比（GMR）=0.76，95%置信区间（CI）0.59-0.98]，而在拉莫三嗪+丙戊酸治疗的患者中，与拉莫三嗪谷浓度升高相关（GMR=1.72，95%CI 1.14-2.62）；（ii）丙戊酸联合治疗总体上与拉莫三嗪单药治疗相比，谷浓度明显升高（GMR=3.49，95%CI 2.73-4.44），但在变异等位基因携带者中升高更为显著（GMR=5.24，95%CI 3.38-8.15），而在野生型纯合子中升高更为显著（GMR=2.32，95%CI 1.89-2.83）；（iii）两种治疗亚组中的变异等位基因作用和两种基因型亚组中的丙戊酸作用差异为 2.36 倍（95%CI 1.39-3.67）；（iv）与丙戊酸谷浓度升高相关的拉莫三嗪谷浓度升高在变异等位基因携带者中大于野生型纯合子，即变异等位基因作用随丙戊酸谷浓度升高而增加。
本研究首次表明 ABCG2 421C>A 多态性与丙戊酸在影响拉莫三嗪分布方面存在潜在的相关相互作用。
