Incorporation and retention of radiolabeled S-(+)- and R-(-)-methamphetamine and S(+)- and R(-)-N-(n-butyl)-amphetamine in mouse hair after systemic administration

We examined the incorporation of unlabeled and tritiated enantiomers of met hamphetamine (MA) and a more lipophilic analog N-(n-butyl)-amphetamine (BA) into the hair of pigmented (C57) and nonpigmented (Balb/C) mice after syst emic administration. We also compared the ability of extraction methods to remove unlabeled and tritiated MA and BA enantiomers from the hair. R(-)-MA , S(+)-MA, [H-3]R(-)-MA, [H-3]S(+)-MA, R(-)-BA, S(+)-BA, [H-3]R-(-)-BA, and [H-3]S-(+)-BA were each administered to C57 and Balb/C mice (23 days of ag e) by i.p. injection at 8.8 mg/kg daily for 3 days. At 44 days of age, hair samples from the animals were treated with a brief methanol wash, a 24-h e xtraction with pH 6 phosphate buffer, and a final digestion in 1 N NaOH to free residual drugs from the hair. Labeled drugs in the extracts were quant itated by liquid scintillation counting. Unlabeled drugs were quantitated b y gas chromatography/mass spectrometry (GC/MS). GC/MS analysis demonstrated MA and BA to be the major (> 90%) species present in the blood during the 24 h after administration. Less than 10% of the MA was N-demethylated. No p -hydroxylated metabolites were found. Blood concentrations of tritiated MA and BA enantiomers measured by liquid scintillation counting agreed well wi th blood concentrations of unlabeled enantiomers measured by GC/MS. Hair co ncentrations of S(+)-MA were greater than those of R(-)-MA in both mouse st rains, paralleling blood concentrations. There were no enantiomeric differe nces seen with BA hair accumulation in either strain of mouse. Significantl y more MA and BA enantiomers were deposited in pigmented than in nonpigment ed hair. With labeled and unlabeled compounds, approximately 30% of S(+)-MA and 60% of R(-)-MA in pigmented hair could be removed by a phosphate extra ction. A significant amount of drug could not be removed from the hair by e xtraction. Greater amounts of drug could be extracted from nonpigmented hai r than pigmented. Extracted and residual MA and BA concentrations in pigmen ted hair were significantly greater when labeled compounds were quantitated by liquid scintillation counting than when unlabeled compounds were quanti tated by GC/MS. However, radiotracer and unlabeled drug concentrations were the same in nonpigmented hair. The results demonstrate that hair pigmentat ion is an important determinant in MA and BA deposition, and that MA and BA deposition is not enantioselective. The data demonstrate a significant amo unt of MA and BA accumulated is not easily amenable to exhaustive aqueous e xtraction from the hair. The use of tritiated MA and BA enantiomers demonst rates that a significant amount of MA and BA stored in pigmented hair is st ructurally different from parent MA and BA, perhaps associated with melanin components of hair.