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Research ArticleArticle

Prediction of Pharmacokinetic Drug/Drug Interactions from In Vitro Data: Interactions of the Nonsteroidal Anti-Inflammatory Drug Lornoxicam with Oral Anticoagulants

Christopher Kohl and Michael Steinkellner
Drug Metabolism and Disposition February 2000, 28 (2) 161-168;
Christopher Kohl
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Michael Steinkellner
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Abstract

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 (Ki = 1.2 ± 0.4 μM) and acenocoumarol (Ki = 5.5 ± 3.5 μM). 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.

Footnotes

  • Send reprint requests to: Dr. Christopher Kohl, Department of Drug Metabolism, Pfizer Central Research, Ramsgate Road, Sandwich, Kent CT13 9NJ, England. E-mail:christopher_kohl{at}sandwich.pfizer.com

  • Abbreviations used are::
    CYP
    cytochrome P-450
    AUC
    area under the plasma concentration-time curve
    NSAID
    nonsteroidal anti-inflammatory drug
    rac
    racemic
    • Received June 28, 1999.
    • Accepted October 12, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 28 (2)
Drug Metabolism and Disposition
Vol. 28, Issue 2
1 Feb 2000
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Research ArticleArticle

Prediction of Pharmacokinetic Drug/Drug Interactions from In Vitro Data: Interactions of the Nonsteroidal Anti-Inflammatory Drug Lornoxicam with Oral Anticoagulants

Christopher Kohl and Michael Steinkellner
Drug Metabolism and Disposition February 1, 2000, 28 (2) 161-168;

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Research ArticleArticle

Prediction of Pharmacokinetic Drug/Drug Interactions from In Vitro Data: Interactions of the Nonsteroidal Anti-Inflammatory Drug Lornoxicam with Oral Anticoagulants

Christopher Kohl and Michael Steinkellner
Drug Metabolism and Disposition February 1, 2000, 28 (2) 161-168;
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