Chiral analysis of d- and l-modafinil in human serum: application to human pharmacokinetic studies.
Modafinil is a novel stimulant approved by the FDA for use in the management of excessive sleepiness associated with narcolepsy. Utility for other indications includes attention deficit-hyperactivity disorder (ADHD), depression, and management of cocaine dependence. To investigate the pharmacokinetics of modafinil in these patients, the authors improved and validated an HPLC method to separate and quantitate the separate enantiomers of modafinil in human serum. d- and l-Modafinil and the internal standard 3,3-diphenylpropylamine were extracted from serum, separated by gradient elution on a beta-cyclodextrin column, and then detected by UV absorbance at 225 nm. The elution gradient was developed to eliminate interferences by other drugs used to manage narcolepsy, ADHD, and stimulants of abuse, and endogenous substances in human serum. Validation studies included determination of stability, selectivity, precision, accuracy, and recovery. The method was used to investigate the pharmacokinetics of d- and l-modafinil in a volunteer after receiving 400 mg twice daily of racemic modafinil for 5 days. Interday and intraday assay variability (CV) typically ranged from 3% to 4%. The limits of detection (0.01 microg/mL) and quantitation (0.5 microg/mL) were well below the concentration expected in serum from patients receiving therapeutic doses of modafinil. The method was free from interference by methylphenidate, cocaine, commonly used antidepressants, and amphetamines. An example of apparent stereoselective disposition is presented as d-modafinil was eliminated more rapidly than l-modafinil from human serum. The validation data support the use of this method for human pharmacokinetic studies of modafinil in patients with known or suspected use of common antidepressants, psychostimulants, and drugs of abuse.
Donovan
Jennifer L
JL
Laboratory of Drug Disposition and Pharmacogenetics, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Malcolm
Robert J
RJ
Markowitz
John S
JS
DeVane
C Lindsay
CL
D001559:Benzhydryl Compounds / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D000697:Central Nervous System Stimulants / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000097:blood; D019970:Cocaine-Related Disorders / Q000378:metabolism; D004347:Drug Interactions; D004355:Drug Stability; D006801:Humans; D008297:Male; D000077408:Modafinil; D011786:Quality Control; D013237:Stereoisomerism
D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D003042:Cocaine; D000077408:Modafinil