Li G, Gong P L, Qiu J, Zeng F D, Klotz U
Department of Clinical Pharmacology, School of Pharmacy, Tongji Medical University, Wuhan/PR China.
Br J Clin Pharmacol. 1998 Nov;46(5):441-5. doi: 10.1046/j.1365-2125.1998.00806.x.
To investigate the steady state disposition and action of racemic propafenone and its enantiomers and the potential for an enantiomer-enantiomer interaction in Chinese subjects.
Eight healthy male Chinese individuals received in a double-blind, randomized, cross-over study racemic propafenone (150 mg every 6 h), (S)-, and (R)-propafenone (150 mg each every 6 h) and placebo orally for 4 days. During the last dosing interval the plasma concentrations of both enantiomers of propafenone were measured and ECG, blood pressure (MAP) and heart rate were monitored.
Whereas the apparent elimination half-life (t1/2,z), mean residence time (MRT) and time to reach peak concentrations (tmax) of (S)- and (R)-propafenone were similar and independent of the administered agent, significant differences were observed in the apparent oral clearance (CLO) of the enantiomers. During dosing with racemic propafenone CLO of (S)- and (R)-propafenone averaged (+/-s.d.) 1226+751 and 1678+625 ml min(-1), respectively (P=0.024). Following the administration of the pure enantiomers CLO of (S)-propafenone increased (P= 0.007) to 2028+/-959 ml min(-1) and that of (R)-propafenone was reduced (P= 0.042) to 1318+/-867 ml min(-1). Both enantiomers and the racemate caused about a 10% increase in the QRS duration (P<0.05) and PR-interval (P<0.01) when compared with placebo. The increase in maximum exercise heart rate was significantly (P<0.05) attenuated only at 3 h following the administration of the racemate and the S-enantiomer. MAP and QTC were not affected significantly.
These data indicate that the stereoselective disposition of propafenone is similar in Chinese and Caucasian subjects (previously published findings), the (R)-enantiomer being cleared more rapidly. A similar enantiomer-enantiomer interaction also occurred. Thus, when the racemate was given, the elimination of (S)-propafenone was impaired and that of the (R)-form accelerated compared with single enantiomer administration. The results indicate that dosage adjustments are probably not required in Chinese patients receiving propafenone.
研究消旋普罗帕酮及其对映体在中国受试者中的稳态处置、作用以及对映体间相互作用的可能性。
8名健康中国男性个体参与一项双盲、随机、交叉研究，口服消旋普罗帕酮（每6小时150毫克）、（S）-普罗帕酮和（R）-普罗帕酮（各每6小时150毫克）以及安慰剂，持续4天。在最后一个给药间隔期间，测定普罗帕酮两种对映体的血浆浓度，并监测心电图、血压（平均动脉压）和心率。
（S）-和（R）-普罗帕酮的表观消除半衰期（t1/2,z）、平均驻留时间（MRT）以及达峰浓度时间（tmax）相似，且与给药制剂无关，但对映体的表观口服清除率（CLO）存在显著差异。在给予消旋普罗帕酮期间，（S）-和（R）-普罗帕酮的CLO平均值（±标准差）分别为1226±751和1678±625毫升/分钟（P = 0.024）。给予纯对映体后，（S）-普罗帕酮的CLO增加（P = 0.007）至2028±959毫升/分钟，而（R）-普罗帕酮的CLO降低（P = 0.042）至1318±867毫升/分钟。与安慰剂相比，两种对映体以及消旋体均使QRS时限（P < 0.05）和PR间期（P < 0.01）增加约10%。仅在给予消旋体和S-对映体后3小时，最大运动心率的增加显著（P < 0.05）减弱。平均动脉压和QTc未受到显著影响。
这些数据表明，普罗帕酮的立体选择性处置在中国人和高加索人受试者中相似（先前已发表的研究结果），（R）-对映体清除更快。类似的对映体间相互作用也会发生。因此，给予消旋体时，与单一对映体给药相比，（S）-普罗帕酮的消除受损，而（R）-形式的消除加速。结果表明，接受普罗帕酮治疗的中国患者可能无需调整剂量。
