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.