Effect of modafinil at steady state on the single-dose pharmacokinetic profile of warfarin in healthy volunteers.
Modafinil has been reported to produce a concentration-related suppression of CYP2C9 activity in vitro in primary cultures of human hepatocytes. To determine whether this effect occurs in vivo, the pharmacokinetics of (S)-warfarin was investigated after single oral doses of racemic warfarin (5 mg; COUMADIN) in a placebo-controlled, single-blind, single-period study in 28 volunteers. Subjects received an oral dose of warfarin prior to administration of modafinil (200 mg for 7 days, followed by 400 mg for 21 days) or placebo and they received another after 4 weeks of treatment. Treatment with modafinil did not significantly alter the pharmacokinetics of (S)- or (R)-warfarin relative to placebo. Since (S)-warfarin is predominantly metabolized via CYP2C9, the results indicate that the marked suppression of CYP2C9 activity in vitro does not translate into a similar effect clinically. However, limitations arising from investigation of single doses of warfarin preclude global conclusions about the potential for more subtle interactions after chronic warfarin administration.
Robertson
Philmore
P
Department of Drug Disposition, Cephalon, Inc., West Chester, Pennsylvania 19380, USA.
Hellriegel
Edward T
ET
Arora
Sanjay
S
Nelson
Michael
M
D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D010349:Patient Compliance; D011517:Prothrombin Time; D016037:Single-Blind Method; D013237:Stereoisomerism; D014859:Warfarin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D000925:Anticoagulants; D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D014859:Warfarin; D000077408:Modafinil