title: Incorporation and retention of radiolabeled S-(+)-and R-(-)-methamphetamine and S(+)- and R(-)-N-(n-butyl)-amphetamine in mouse hair after systemic administration.
abstract: We examined the incorporation of unlabeled and tritiated enantiomers of methamphetamine (MA) and a more lipophilic analog N-(n-butyl)-amphetamine (BA) into the hair of pigmented (C57) and nonpigmented (Balb/C) mice after systemic 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, [(3)H]R(-)-MA, [(3)H]S(+)-MA, R(-)-BA, S(+)-BA, [(3)H]R-(-)-BA, and [(3)H]S-(+)-BA were each administered to C57 and Balb/C mice (23 days of age) 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 extraction 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 quantitated by liquid scintillation counting. Unlabeled drugs were quantitated by 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 with blood concentrations of unlabeled enantiomers measured by GC/MS. Hair concentrations of S(+)-MA were greater than those of R(-)-MA in both mouse strains, paralleling blood concentrations. There were no enantiomeric differences seen with BA hair accumulation in either strain of mouse. Significantly more MA and BA enantiomers were deposited in pigmented than in nonpigmented 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 extraction. A significant amount of drug could not be removed from the hair by extraction. Greater amounts of drug could be extracted from nonpigmented hair than pigmented. Extracted and residual MA and BA concentrations in pigmented hair were significantly greater when labeled compounds were quantitated by liquid scintillation counting than when unlabeled compounds were quantitated by GC/MS. However, radiotracer and unlabeled drug concentrations were the same in nonpigmented hair. The results demonstrate that hair pigmentation is an important determinant in MA and BA deposition, and that MA and BA deposition is not enantioselective. The data demonstrate a significant amount of MA and BA accumulated is not easily amenable to exhaustive aqueous extraction from the hair. The use of tritiated MA and BA enantiomers demonstrates that a significant amount of MA and BA stored in pigmented hair is structurally different from parent MA and BA, perhaps associated with melanin components of hair.
authors.affiliation: University of Colorado Health Sciences Center, Department of Molecular Toxicology and Environmental Health Sciences, Denver, Colorado 80262, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Stout
authors.forename: D J
authors.initials: DJ
authors.lastname: Claffey
authors.forename: J A
authors.initials: JA
authors.lastname: Ruth
mesh_terms: D000661:Amphetamine / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D000697:Central Nervous System Stimulants / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008401:Gas Chromatography-Mass Spectrometry; D006197:Hair / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008694:Methamphetamine / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013237:Stereoisomerism; D014018:Tissue Distribution; D014316:Tritium
chemical_list: D000697:Central Nervous System Stimulants; D014316:Tritium; D008694:Methamphetamine; D000661:Amphetamine