| Description |
The plasma disposition of L-alpha-acetylmethadol (LAAM) and its two active metabolites, nor-LAAM and dinor-LAAM, has been determined in 12 human subjects as part of a controlled clinical pharmacological study. LAAM was administered orally three times per week for ten doses, ranging from 0.73 mg/kg to 1.51 mg/kg (80 mg doses), with five subjects receiving 1.0 mg/kg. Plasma concentrations were followed at short intervals after the first three and last doses and for a total of approximately 1000 hr, where possible. A new quantitative, specific, and very sensitive analytical method was developed for the study and is reported in detail. The method involves organic solvent extraction, amide-derivative formation of the metabolites, and gas chromatography-chemical ionization-multiple ion monitoring-quadrupole mass spectrometry, with methane as carrier and ammonia as reagent gases. Deuterated stable isotopes of LAAM and the two metabolites are used as internal standards. The method has quantitative sensitivity to 5 ng/ml for a 2.0 ml plasma sample with 10-15% accuracy and precision. For the range used in the study, the dose of LAAM is not a critical variable with respect to ultimate plasma concentrations achieved and cannot be used to predict maximum concentrations or the possibility of drug or metabolite accumulation. The mean time taken to reach maximum plasma concentration after the first dose of LAAM was 4.4 hr; for nor-LAAM, 5.6 hr; and for dinor-LAAM, 6.6 hr. There was no change in these values after the tenth and final dose. Maximum concentrations after the first dose varied from 52 to 510 ng/ml for LAAM; 65-175 ng/ml for nor-LAAM; and 11-92 ng/ml for dinor-LAAM. Three subjects continuously accumulated LAAM and both metabolites; these three plus two others accumulated LAAM, and the five plus one other accumulated dinor-LAAM. The other six subjects reached plateau concentrations after the anticipated 4-5 half-lives of elimination. The mean half-lives in hours were LAAM t1/2alpha 2.4, t1/2beta 37.5 (first dose), t1/2beta 46.8 (last dose); nor-LAAM, t1/2beta 38.2 (first dose), t1/2beta 64.6 (last dose); dinor-LAAM, t1/2beta 168 (last dose). The maximum plasma concentrations increased over the ten-dose period by a factor of approximately 2.0 for LAAM, 2.0-4.0 for nor-LAAM, and 4.0-10.0 for dinor-LAAM. The t1/2beta for LAAM was independent of dose throughout the study, and the plasma concentration-time-course profiles are generally consistent with a two-compartment, first-order kinetic model. |
