Prediction of pharmacokinetic drug/drug interactions from In vitro data: interactions of the nonsteroidal anti-inflammatory drug lornoxicam with oral anticoagulants.
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.
Kohl
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C
Department of Drug Disposition, Nycomed Austria, Linz, Austria. christopher_kohl@sandwich.pfizer.com
Steinkellner
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M
D000074:Acenocoumarol / Q000493:pharmacokinetics / Q000494:pharmacology; D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000925:Anticoagulants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000378:metabolism; D010644:Phenprocoumon / Q000493:pharmacokinetics / Q000494:pharmacology; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D011237:Predictive Value of Tests; D014859:Warfarin / Q000493:pharmacokinetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D010894:Piroxicam; D014859:Warfarin; C059451:lornoxicam; D000074:Acenocoumarol; D010644:Phenprocoumon; C032801:tenoxicam