Trenk D, Möhrke W, Warth L, Jähnchen E
Department of Clinical Pharmacology, Rehabilitationszentrum, Bad Krozingen, Fed. Rep. of Germany.
Arzneimittelforschung. 1993 Aug;43(8):836-41.
The investigational antiarrhythmic drug LNC-834 ((9S)-10,11-dihydro-6'-methoxy-cinchonan-3,9-diol hydrogen sulfate pentahydrate, CAS 85405-59-0) is structurally related to quinidine. It was investigated, if concurrent administration of LNC-834 affects the single dose pharmacokinetics and pharmacodynamics of warfarin (CAS 81-81-2). The study was performed as an open, randomized two-way cross-over, controlled investigation in 10 healthy volunteers. In treatment A, 2 tablets of LNC-834 (350 mg of hydrated salt corresponding to 226 mg anhydrous free base each) were ingested twice daily for a period of 9 days in total. On the 4th study day, 2 h after the application of LNC-834 in the morning, the volunteers received a mean dose of 0.36 +/- 0.03 mg/kg warfarin orally. In treatment B only warfarin was administered. Pharmacokinetics of warfarin and anticoagulant effect (prothrombin complex activity) were determined from plasma samples withdrawn up to 144 h after administration; LNC-409 (free base of LNC-834) and the metabolite LNC-253 (2'-oxo-analog) were monitored for check of compliance over the same time period. Concurrent administration of LNC-834 decreased significantly the area under the plasma concentration-time curve of warfarin (117,889 +/- 25,010 (A) vs. 125,294 +/- 22,314 ng/ml.h (B); p = 0.0488). Thus, a significant increase in apparent oral clearance (CL/f) of warfarin in the presence of LNC-834 was determined (3.98 +/- 0.63 vs. 3.71 +/- 0.50 ml/min; p = 0.0488). All other pharmacokinetic parameters determined (apparent volume of distribution (V/f), Cmax, tmax, terminal half-life of elimination) were not altered by concurrent treatment with LNC-834.(ABSTRACT TRUNCATED AT 250 WORDS)
研究性抗心律失常药物LNC - 834（(9S)-10,11 - 二氢 - 6'-甲氧基 - 金鸡纳 - 3,9 - 二醇硫酸氢盐五水合物，CAS 85405 - 59 - 0）在结构上与奎尼丁相关。研究了同时给予LNC - 834是否会影响华法林（CAS 81 - 81 - 2）的单剂量药代动力学和药效学。该研究在10名健康志愿者中作为一项开放、随机的双向交叉对照研究进行。在治疗A中，每天两次服用2片LNC - 834（每片350 mg水合盐，相当于226 mg无水游离碱），共9天。在研究第4天，早晨服用LNC - 834 2小时后，志愿者口服平均剂量为0.36±0.03 mg/kg的华法林。在治疗B中，仅给予华法林。在给药后长达144小时采集的血浆样本中测定华法林的药代动力学和抗凝效果（凝血酶原复合物活性）；在同一时间段监测LNC - 409（LNC - 834的游离碱）和代谢物LNC - 253（2'-氧代类似物）以检查依从性。同时给予LNC - 834显著降低了华法林的血浆浓度 - 时间曲线下面积（(117,889±25,010 (A) 与125,294±22,314 ng/ml·h (B)；p = 0.0488）。因此，确定在存在LNC - 834的情况下华法林的表观口服清除率（CL/f）显著增加（3.98±0.63与3.71±0.50 ml/min；p = 0.0488）。所测定的所有其他药代动力学参数（表观分布容积（V/f）、Cmax、tmax、消除终末半衰期）在与LNC - 834同时治疗时未改变。（摘要截短于250字）
