Brar Satjit, Vijan Arjun, Scott Fiona L, Jimenez Roland, Zhang Hui, Grigoriadis Dimitri E, Loewen Gordon
Neurocrine Biosciences, Inc., San Diego, California, USA.
Clin Pharmacol Drug Dev. 2023 Apr;12(4):447-456. doi: 10.1002/cpdd.1205. Epub 2022 Dec 18.
Valbenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors approved for tardive dyskinesia. The clinical activity of valbenazine is primarily attributed to its only dihydrotetrabenazine (HTBZ) metabolite, [+]-α-HTBZ. Deutetrabenazine is a deuterated form of tetrabenazine and is metabolized to four deuterated HTBZ metabolites: [+]-α-deuHTBZ, [+]-β-deuHTBZ, [-]-α-deuHTBZ, and [-]-β-deuHTBZ. An open-label, crossover study characterized the pharmacokinetic profiles of the individual deuHBTZ metabolites, which have not been previously reported. VMAT2 inhibition and off-target interactions of the deuHTBZ metabolites were evaluated using radioligand binding. The only valbenazine HTBZ metabolite, [+]-α-HTBZ, was a potent VMAT2 inhibitor, with negligible affinity for off-target dopamine, serotonin, and adrenergic receptors. Following deutetrabenazine administration, [-]-α-deuHTBZ represented 66% of circulating deuHTBZ metabolites and was a relatively weak VMAT2 inhibitor with appreciable affinity for dopamine (D , D ) and serotonin (5-HT , 5-HT , 5-HT ) receptors. [+]-β-deuHTBZ was the most abundant deuHTBZ metabolite that potently inhibited VMAT2, but it represented only 29% of total circulating deuHTBZ metabolites. The mean half-life of [+]-α-HTBZ (22.2 hours) was ∼3× longer than that of [+]-β-deuHTBZ (7.7 hours). These findings are similar to studies with tetrabenazine, in that deutetrabenazine is metabolized to four deuHTBZ stereoisomers, the most abundant of which has negligible interaction with VMAT2 in vitro and appreciable affinity for several off-target receptors. In contrast, valbenazine's single HTBZ metabolite is a potent VMAT2 inhibitor in vitro with no discernible off-target activity. Determination of the effects of intrinsic/extrinsic variables on deutetrabenazine's safety/efficacy profile should incorporate assessment of the effects on all deuHTBZ metabolites.
缬苯那嗪和氘代丁苯那嗪是已被批准用于治疗迟发性运动障碍的囊泡单胺转运体2（VMAT2）抑制剂。缬苯那嗪的临床活性主要归因于其唯一的二氢丁苯那嗪（HTBZ）代谢物[+]-α-HTBZ。氘代丁苯那嗪是丁苯那嗪的氘代形式，可代谢为四种氘代HTBZ代谢物：[+]-α-氘代HTBZ、[+]-β-氘代HTBZ、[-]-α-氘代HTBZ和[-]-β-氘代HTBZ。一项开放标签的交叉研究对之前未报道过的各氘代HTBZ代谢物的药代动力学特征进行了描述。使用放射性配体结合法评估了氘代HTBZ代谢物的VMAT2抑制作用和脱靶相互作用。缬苯那嗪唯一的HTBZ代谢物[+]-α-HTBZ是一种强效VMAT2抑制剂，对脱靶多巴胺、5-羟色胺和肾上腺素能受体的亲和力可忽略不计。服用氘代丁苯那嗪后，[-]-α-氘代HTBZ占循环中氘代HTBZ代谢物的66%，是一种相对较弱的VMAT2抑制剂，对多巴胺（D ，D ）和5-羟色胺（5-HT ，5-HT ，5-HT ）受体具有明显亲和力。[+]-β-氘代HTBZ是最丰富的氘代HTBZ代谢物，能有效抑制VMAT2，但仅占循环中总氘代HTBZ代谢物的29%。[+]-α-HTBZ的平均半衰期（22.2小时）比[+]-β-氘代HTBZ（7.7小时）长约3倍。这些发现与丁苯那嗪的研究结果相似，即氘代丁苯那嗪代谢为四种氘代HTBZ立体异构体，其中最丰富的异构体在体外与VMAT2的相互作用可忽略不计，但对几种脱靶受体具有明显亲和力。相比之下，缬苯那嗪单一的HTBZ代谢物在体外是一种强效VMAT2抑制剂，没有可识别的脱靶活性。确定内在/外在变量对氘代丁苯那嗪安全性/疗效的影响时，应纳入对所有氘代HTBZ代谢物影响的评估。
