acenocoumarol and lornoxicam

To investigate the effect of lornoxicam co-administration on acenocoumarol pharmacokinetics and pharmacodynamics.. In an open crossover study, six healthy male volunteers received racemic acenocoumarol (10 mg) orally without/with lornoxicam co-administration (8 mg twice daily).. The median (range) areas under the concentration-time curve (AUC) for (R)-acenocoumarol were 3458 (3035-7312) microg x h 1(-1) in the absence of and 3667 (2907-7741) microg x h 1(-1) in the presence of lornoxicam. The corresponding values for (S)-acenocoumarol were 479 (381-853) microg x h 1(-1) and 612 (425-1241) microg x h 1(-1). The differences were not statistically significant. Lornoxicam co-administration did not influence the free fractions or acenocoumarol's effect on factor II and VII activities. Simulations based on the results of a model-based analysis predicted that in the case of lornoxicam co-administration, the factor VII activity of a person in steady-state at 26% will remain between 14% and 32%.. Co-administration of lornoxicam at the upper limit of recommended doses does not alter the pharmocokinetics of the clinically relevant (R)-acenocoumarol or the anticoagulant activity of acenocoumarol. These data clearly differ from the results of previous studies, which showed clinically relevant influences of lornoxicam on warfarin kinetics and of piroxicam on acenocoumarol kinetics.

Topics: Acenocoumarol; Adult; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Cross-Over Studies; Drug Interactions; Half-Life; Humans; Male; Models, Biological; Piroxicam

CYP2C9 is involved in the metabolism of the oral anticoagulants warfarin, phenprocoumon, and acenocoumarol. It is also responsible for the 5'-hydroxylation of the nonsteroidal anti-inflammatory drug lornoxicam. Therefore, lornoxicam and the oral anticoagulants are potential inhibitors of their metabolism. Their inhibitory potency was investigated in microsomes from six human livers. An approach to predict pharmacokinetic interactions of lornoxicam from in vitro inhibition data was developed. Where possible, the forecasts were verified by comparison with data from clinical interaction studies. The following increases in steady-state plasma concentrations or areas under the plasma concentration-time curve of the oral anticoagulants by concomitant lornoxicam medication were predicted (values in parentheses are for healthy volunteers): (S)-warfarin, 1. 58-fold (1.32-fold for racemate); racemic-acenocoumarol, 1.28-fold (1.09-fold); (R)-acenocoumarol, 1.10-fold (1.0-fold); racemic-phenprocoumon, 1.11-fold (1.18-fold); and (S)-phenprocoumon, 1.13-fold (1.24-fold). Lornoxicam 5'-hydroxylation was competitively inhibited in vitro by both phenprocoumon (K(i) = 1.2 +/- 0.4 microM) and acenocoumarol (K(i) = 5.5 +/- 3.5 microM). The present results indicate that relatively close predictions of the interactions of lornoxicam with oral anticoagulants from in vitro data are possible under the assumption that hepatic lornoxicam concentrations are similar to its total plasma concentrations. The degree of pharmacokinetic interactions exhibited by oral anticoagulants and lornoxicam is dependent on the respective contribution of CYP2C9 to their total clearance.

Topics: Acenocoumarol; Algorithms; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Area Under Curve; Chromatography, High Pressure Liquid; Drug Interactions; Humans; In Vitro Techniques; Microsomes, Liver; Phenprocoumon; Piroxicam; Predictive Value of Tests; Warfarin