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Determination of l-alpha-acetylmethadol (LAAM), norLAAM, and dinorLAAM in clinical and in vitro samples using liquid chromatography with electrospray ionization and tandem mass spectrometry.

l-Alpha-acetylmethadol (LAAM) is an alternative to methadone for the maintenance treatment of opioid dependence. LAAM has a longer therapeutic half-life than methadone, primarily because it is metabolized to more active metabolites, norLAAM and dinorLAAM. We have developed a liquid chromatography-tandem mass spectrometry method capable of measuring LAAM and its metabolites, norLAAM and dinorLAAM, at lower concentrations with 1.0-mL aliquots of plasma (range of 0.25 to 100 ng/mL) or higher concentration with 0.2-mL aliquots of plasma (range 1.25 to 500 ng/mL). It has acceptable precision and accuracy across both linear ranges, as well as in the urine matrix. Results from this assay correlate well with our previously validated gas chromatograghy-mass spectrometry method. All analytes had acceptable stability after three freeze-thaw cycles, room temperature storage for 20 h, or storage of extracts either at -20 degrees C for 6 days or on the autosampler (10 degrees C) for 4 days. The pharmacokinetics of LAAM, norLAAM, and dinorLAAM were determined for the first time in three male opioid-naive individuals receiving a single oral dose of 5 mg LAAM/70 kg. Using this method, we could monitor the in vitro N-demethylation of LAAM and norLAAM at substrate concentrations in the therapeutic range of 0.5 and 1.0 microM by cDNA-expressed cytochrome P450s. This confirmed the involvement of cytochrome P450s 3A4, 2B6, 2C8, and 2C18 at therapeutic concentrations of LAAM. An accurate and precise method for determination of LAAM and its metabolites, norLAAM and dinorLAAM, that is suitable for both in vivo and in vitro metabolism studies has been developed and validated.