2017 Volume 43 Issue 7 Pages 362-372
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.
