Impact of the Catechol-O-Methyltransferase Val158Met Polymorphism on the Pharmacokinetics of L-dopa and its Metabolite 3-O-Methyldopa in Combination with Entacapone （エンタカポン併用下におけるL-dopaおよびその代謝物である3-O-メチルドパの体内動態に及ぼすカテコール-O-メチルトランスフェラーゼVal158Met遺伝子多型の影響に関する研究）
著者
山本, 譲
(Yamamoto, Joe)
上位タイトル
Journal of Neural Transmission
Vol.128,
No.1
(2021.
1)
,p.27-
36
識別番号
ISSN
0300-9564
DOI
10.1007/s00702-020-02267-y
その他
PMID:33136226
博士論文情報
学位授与番号
10107B490
学位授与年月日
2021-09-30
学位名
博士（医学）
学位授与機関
旭川医科大学
抄録
In the pharmacotherapy of patients with Parkinson's disease (PD), entacapone reduces the peripheral metabolism of L-dopa to 3-O-methyldopa (3-OMD), thereby prolonging the half-life (t1/2) of L-dopa and increasing the area under the concentration curve (AUC). The effect of entacapone on the pharmacokinetics of L-dopa differs between patients with high-activity (H/H) and low-activity (L/L) catechol-O-methyltransferase (COMT) Val158Met polymorphisms, but the effects are unclear in heterozygous (H/L) patients. 3-OMD has a detrimental effect and results in a poor response to L-dopa treatment in patients with PD; however, the influence of this polymorphism on the production of 3-OMD remains unknown. Therefore, the present study aimed to clarify the effect of the COMT Val158Met polymorphism on the concentrations of L-dopa and 3-OMD in the presence of entacapone. We performed an open-label, single-period, single-sequence crossover study at two sites in Japan. The study included 54 Japanese patients with PD, who underwent an acute L-dopa administration test with and without 100 mg entacapone on two different days. Entacapone increased L-dopa AUC0-infinity by 1.59 ± 0.26-fold in the H/H group, which was significantly higher than that in the H/L (1.41 ± 0.36-fold) and L/L (1.28 ± 0.21-fold) groups (p < 0.05). The concurrent administration of L-dopa with entacapone suppressed the increase in 3-OMD levels compared with L-dopa alone in all genotypes. Our results suggest that the COMT Val158Met polymorphism may be an informative biomarker for individualized dose adjustment of COMT inhibitors in the treatment of PD.
