双極性障害患者のラモトリギン血中濃度に影響を与える因子の解析

抄録

This study analyzed factors affecting plasma lamotrigine (LTG) concentrations in patients with bipolar disorder. The mean concentration/dose (C/D) ratio of LTG was significantly higher in patients co-treated with LTG and valproic acid (VPA) [3.72 (μg/mL)/(mg/kg/day), n = 9] than in those receiving LTG monotherapy [1.76 (μg/mL)/(mg/kg/day), n = 9; P < 0.01]. LTG monotherapy patients were genotyped for UDP-glucuronosyltransferase 2B7 (UGT2B7) ^＊1/^＊1 (n = 5) and ^＊1/^＊2(n = 4), whereas VPA co-administration patients were genotyped for UGT2B7^＊1/^＊1 (n = 6), ^＊1/^＊2 (n = 2) and ^＊2/^＊2 (n = 1). _＊There were no significant differences in mean C/D ratios between patients carrying the UGT2B7^＊1/^＊1 genotype and the 1/^＊2 or ^＊2/^＊2 genotype regardless of pharmacotherapy (P ≥ 0.150). In the LTG monotherapy group, the mean C/D ratio was similar in smoking patients [1.52 (μg/mL)/(mg/kg/day), n = 3] and non-smoking patients [1.88 (μg/mL)/(mg/kg/day), n = 6; P = 0.393]. In the VPA co-administration group, however, the mean C/D ratio in smoking patients [2.62 (μg/mL)/(mg/kg/day), n = 4] was significantly lower than that in non-smoking patients [4.61 (μg/mL)/(mg/kg/day), n = 5; P < 0.01]. In vitro studies with HepG2 cells indicated that benzo[a]pyrene, one of the polycyclic aromatic hydrocarbons contained in tobacco smoke, as well as 3-methylcholanthrene efficiently induced expression of UGT1A4 mRNA but not UGT2B7 mRNA and that VPA potently enhanced their induction. These results suggest that concomitant VPA administration and/or smoking may influence LTG concentrations in patients with bipolar disorder.