中国健康志愿者普罗帕酮的药代动力学及与异喹胍，美芬妥英代谢多态性的相关性研究

Pharmacokinetics of propafenone and its relationship withdebrisoquin and mephenytoin metabolism polymorphismsin healthy Chinese volunteers1

应用高效液相色谱法及气相色谱法，研究了９名健康志愿者口服单剂量普罗帕酮的药代动力学及与异喹胍，Ｓ－美芬妥英羟化代谢多态性的相关性。结果表明，６名志愿者中普罗帕酮按一房室模型消除，其余３名符合二房室模型。普罗帕酮消除半衰期为３．４±ｓ１．１ｈ，药时曲线下面积为２．５±ｓ１．１μｇ·＝ｍＬ１，血浆清除率为１４５±ｓ６４Ｌ·ｈ１．普罗帕酮药代动力学参数在异喹胍强与弱代谢者中有较大的差异，而与Ｓ－美芬妥英不同羟化代谢表型则无明显相关性．同时服用普罗帕酮和异喹胍时，两药氧化代谢可产生互相抑制性影响．而普罗帕酮与Ｓ－美芬妥英公用则无明显改变。

After a single oral dose of 300 mgpropafenone, its pharmacokinetics was studied in 9healthy Chinese volunteers, including 8 extensivemetabolizers (EMs) and 1 poor metabolizer (PM) ofdebnsoquin (DB). or 6 EMs and 3 PMs ofmephenytoin (MP) hydroxylation phenotypes. Also,the relationships between propafenone metabolism andDB or MP hydroxylation polymorphism were investigated. The concentration time curve of propafenoneshowed that it was eliininated as onecompartmentmodel in 6 volunteers and as twocompartment modelin the other 3. The elimination half-life of propa-fenone was 3.4 ± s 1 . 1 h. the area under the concentra-tion time curve (AUC) was 2. 5 ±s 1 . 1 Pg . h 1 . m L 1 .and the svstemic clearance was 145 ±s 64 L . h 1. Thephaimacokinctic parameters of propafenone inDBEM tend to be different from those in theDBPM. but not in MPEM and MPPM, indicatingthat propafenone metabolism might not cosegregatewith mephenytoin 4hydroxylation polymorphism.When coadministrating propafenone with 10 mg DB.the pharmacokinetic parameters of DB and its 4-hy-droxylated metabolite were profoundly altered inDBEM, but less significantly in the DBPM. Theplasma concentration of propafenone increasedsignificantly in the presence of DB (P0<0.05). Theinhibitory effects of DB and propatenone on themctabolism ofeach other suggest that they inay be oxi-dized by the same hepatic cytochronle P450isoenzvmes in Chinese volunteers.