Armodafinil, the R-enantiomer of modafinil: wake-promoting effects and pharmacokinetic profile in the rat.
Modafinil reduces the excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. In rats, modafinil promotes dose-dependent increases in wake duration. The wake-promoting activity of the R-enantiomer of modafinil (armodafinil) was evaluated in WKY rats and compared to the classical stimulant, D-methamphetamine. Electroencephalographic and electromyographic signals were assessed via a tethered cranial implant. Body temperature and locomotor activity were assessed by telemetry via intraperitoneal implant. Rats (n=60, 12 per group) were subjected to one of five parallel treatments: armodafinil at 30, 100 and 300 mg/kg i.p.; D-methamphetamine, 1 mg/kg i.p. and vehicle. Armodafinil and D-methamphetamine increased time spent awake relative to vehicle. Armodafinil-evoked increases in wake duration were dose-dependent and proportional to plasma compound exposure. Induction of wakefulness by D-methamphetamine was associated with an approximately two-fold increase in locomotor activity during the 2-h period immediately following administration relative to vehicle. D-methamphetamine also increased body temperature over the same time interval. The dose of armodafinil (100 mg/kg, i.p.) that was closest to D-methamphetamine in its wake-promoting efficacy did not produce changes in either body temperature or the intensity of locomotor activity relative to vehicle. Acute rebound hypersomnolence, characterized by increases in non-rapid eye movement sleep (NREMS) as a percentage of time and NREMS bout duration and by a decreased frequency of brief awakenings following sleep deprivation, occurred following D-methamphetamine-but not armodafinil-induced wake in this rat model which has been shown to be predictive of human drug responses.
Wisor
Jonathan P
JP
Stanford Sleep Disorders Clinic and Research Laboratory, 701 Welch Rd., Suite 2226, Stanford, CA 94304, USA.
Dement
William C
WC
Aimone
Lisa
L
Williams
Michael
M
Bozyczko-Coyne
Donna
D
D000818:Animals; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY; D012894:Sleep Stages / Q000187:drug effects; D013237:Stereoisomerism; D014851:Wakefulness / Q000187:drug effects*
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D000077408:Modafinil