Dingemanse J, Jorga K M, Schmitt M, Gieschke R, Fotteler B, Zürcher G, Da Prada M, van Brummelen P
Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Clin Pharmacol Ther. 1995 May;57(5):508-17. doi: 10.1016/0009-9236(95)90035-7.
To assess the tolerability, pharmacokinetics and pharmacodynamics of single oral doses of the novel catechol-O-methyltransferase (COMT) inhibitor tolcapone in healthy volunteers.
In this double-blind, placebo-controlled, ascending-single-dose study, doses of 5 to 800 mg tolcapone were administered orally to eight sequential groups of six young healthy male volunteers. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of tolcapone and its 3-O-methylmetabolite were determined. Pharmacodynamics were assessed by determination of COMT activity in erythrocytes.
Tolcapone was well tolerated at all dose levels and did not exert a detectable influence on vital sign measurements. The drug was rapidly absorbed and showed dose-proportional pharmacokinetics. Its mean elimination half-life was 2.0 +/- 0.8 hours (n = 42). Plasma levels of the 3-O-methylmetabolite of tolcapone were not proportional to dose, and its formation was delayed at higher doses. Its elimination half-life was 32 +/- 7 hours (n = 29). Tolcapone caused a rapid and reversible inhibition of COMT activity in erythrocytes. At doses of 200 mg and higher, COMT activity was inhibited by more than 80%. The pharmacokinetic-pharmacodynamic relationship could be described by an inhibitory Emax model and suggested that metabolites of tolcapone did not substantially contribute to its inhibitory activity.
The novel COMT inhibitor tolcapone was well tolerated at oral doses of 5 to 800 mg. Tolcapone concentration-dependently inhibited COMT activity in erythrocytes and exhibited dose-proportional kinetics. Further investigations into its applicability in the treatment of Parkinson's disease are warranted.
评估新型儿茶酚-O-甲基转移酶（COMT）抑制剂托卡朋单次口服剂量在健康志愿者中的耐受性、药代动力学和药效学。
在这项双盲、安慰剂对照、单剂量递增研究中，依次对八组每组六名年轻健康男性志愿者口服5至800毫克托卡朋。记录不良事件、生命体征和临床实验室指标。测定托卡朋及其3-O-甲基代谢物的药代动力学参数。通过测定红细胞中的COMT活性评估药效学。
托卡朋在所有剂量水平下耐受性良好，对生命体征测量未产生可检测到的影响。该药物吸收迅速，呈现剂量比例药代动力学。其平均消除半衰期为2.0±0.8小时（n = 42）。托卡朋的3-O-甲基代谢物的血浆水平与剂量不成比例，且在较高剂量下其形成延迟。其消除半衰期为32±7小时（n = 29）。托卡朋可迅速且可逆地抑制红细胞中的COMT活性。在200毫克及更高剂量下，COMT活性被抑制超过80%。药代动力学-药效学关系可用抑制性Emax模型描述，提示托卡朋的代谢物对其抑制活性贡献不大。
新型COMT抑制剂托卡朋在5至800毫克口服剂量下耐受性良好。托卡朋浓度依赖性地抑制红细胞中的COMT活性，并呈现剂量比例动力学。有必要进一步研究其在帕金森病治疗中的适用性。
