Stereoselective interaction between piroxicam and acenocoumarol

1 An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers.
2 Eight healthy male volunteers received an oral dose of 4  mg rac -acenocoumarol on days 1 and 8, plus 40  mg piroxicam orally 2  h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24  h interval.
3 The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: C _max+28.0% (s.d.23.8), P <0.05; AUC(0,  24  h)+47.2% (21.5), P <0.005; and t _1/2+38.0% (34.5), P <0.01. A concomitant decrease of CL/ F was observed: ?30.8% (10.0), P <0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: C _max: +9.5% (s.d.36.6), AUC(0,  24  h): +15.4% (23.4), t _1/2: +19.9% (42.0), and CL/ F: ?9.8% (20.5). V/F remained unchanged for both enantiomers.
4 Piroxicam plasma AUC(0,  24  h) correlated closely with R- and Sacenocoumarol AUCs on day 1 ( r =0.901, P <0.005 and r =0.797, P <0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol ( r =0.903, P <0.001) and S-acenocoumarol ( r =0.711, P <0.05).
5 Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.