Prediction of pharmacokinetic drug/drug interactions from in vitro data: Interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oralanticoagulants

CYP2C9 is involved in the metabolism of the oral anticoagulants warfarin, p henprocoumon, and acenocoumarol. It is also responsible for the 5'-hydroxyl ation of the nonsteroidal anti-inflammatory drug lornoxicam. Therefore, lor noxicam and the oral anticoagulants are potential inhibitors of their metab olism. Their inhibitory potency was investigated in microsomes from six hum an livers. An approach to predict pharmacokinetic interactions of lornoxica m from in vitro inhibition data was developed. Where possible, the forecast s were verified by comparison with data from clinical interaction studies. The following increases in steady-state plasma concentrations or areas unde r the plasma concentration-time curve of the oral anticoagulants by concomi tant lornoxicam medication were predicted (values in parentheses are for he althy volunteers): (S)-warfarin, 1.58-fold (1.32-fold for racemate); racemi c-acenocoumarol, 1.28-fold (1.09-fold); (R)-acenocoumarol, 1.10-fold (1.0-f old); racemic-phenprocoumon, 1.11-fold (1.18-fold); and (S) phenprocoumon, 1.13-fold (1.24-fold). Lornoxicam 5'-hydroxylation was competitively inhibi ted in vitro by both phenprocoumon (K-i = 1.2 +/- 0.4 mu M) and acenocoumar ol (K-i = 5.5 +/- 3.5 mu M). The present results indicate that relatively c lose predictions of the interactions of lornoxicam with oral anticoagulants from in vitro data are possible under the assumption that hepatic lornoxic am concentrations are similar to its total plasma concentrations. The degre e of pharmacokinetic interactions exhibited by oral anticoagulants and lorn oxicam is dependent on the respective contribution of CYP2C9 to their total clearance.