Stereoselective interaction between piroxicam and acenocoumarol

1An open‐label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers.

2Eight 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.

3The 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.

4Piroxicam 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).

5Piroxicam 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.

DOI: 10.1046/j.1365-2125.1996.03558.x

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