Determination of the interaction of 3S-hydroxy-10,11-dihydroquinidine on the pharmacokinetics and pharmacodynamics of warfarin.

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of warfarin and anticoagulant effect (prothrombin complex activity) were determined from plasma samples withdrawn up to 144 h after administration; LNC-409 (free base of LNC-834) and the metabolite LNC-253 (2'-oxo-analog) were monitored for check of compliance over the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)