新しい抗不整脈薬ｐｉｒｍｅｎｏｌの薬物動態および心室期外収縮抑制効果

Abstract

The pharmacokinetics of pirmenol hydrochloride (pirmenol), a new antiarrhythmic agent, and its suppressive effects on ventricular premature contractions (VPC) were studied in 16 patients following single oral administration of 75mg, 100mg, and 150mg of the drug. In 8 of 16 patients, suppressive effects on VPC were also studied following multiple oral administration of pirmenol of 75mg b. i. d. or 100mg b. i. d. Blood samples were drawn before and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 48hr after single oral administration. In the multiple oral administration study, blood samples were collected before and 2hr after morning dose during the treatment period. Plasma and urine drug concentration were measured using high performance liquid chromatography (HPLC). Plasma protein binding of pirmenol was determined by an ultrafiltration method. A 48-hr continuous ECG and standard 12-lead ECGs were recorded to assess the effects of pirmenol on VPC and ECG parameters.The Cmax and AUC after single administration were 0.799μg/ml & 9.23μg·hr/ml in 75mg group (n=6), 0.784μg/ml & 11.23μg·hr/ml in 100mg group (n=6) and 1.156μg/ml & 15.70μg·hr/ml in 150mg group (n=4), respectively. The Cmax and AUC increased in a dose-dependent manner. The Tmax, t1/2 β, urinary excretion rate and protein binding rate were independent of the dosage. The Cmax and Cmin at the steady state during multiple administration were 1.149 & 0.235μg/ml in 75mg b. i. d. group (n=2) and 1.472 & 0.598μg/ml in 100mg b. i, d, group (n=6). Suppressive effects of pirmenol on VPC were observed in 5 out of 12 patients with more than 3, 000VPC/day in the single administration study and also in 3 out of 4 patients in the multiple administration study. The minimum effective plasma concentration of pirmenol was 0.361±0.133μg/ml. The PQ & QT interval and QTc were prolonged significantly after single and multiple administration. Serious adverse events were not observed in any patients during the study.We conclude that pirmenol is a useful antiarrhythmic agent for the treatment on VPC, and that 100mg b. i, d, is safe and suitable for chronic management of the patients with frequent VPC.