Tissue concentrations of MPTP and MPP+ after administration of lethal and sublethal doses of MPTP to mice.
Tissue concentrations of MPP+ (1-methyl-4-phenylpyridinium) were measured in Charles River CFW mice after administration of high doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or MPP+ given subcutaneously or orally, to investigate the relationships between tissue concentrations and lethality resulting from these compounds. MPTP given subcutaneously led to much higher concentrations of MPP+ in brain and somewhat higher concentrations of MPP+ in peripheral tissues than did MPTP given orally. MPTP caused no lethality at oral doses up to 160 mg/kg whereas subcutaneous MPTP had an LD50 of 54 mg/kg. Deprenyl pretreatment antagonized the lethality of subcutaneous MPTP and reduced MPP+ concentrations in brain and in other tissues after MPTP injection. Deprenyl caused a greater and longer-lasting inhibition of MPTP oxidation than of phenylethylamine oxidation, especially in liver, although both compounds are thought to be oxidized by monoamine oxidase type B. The protective effect of deprenyl against MPTP lethality implicates MPP+ (or possibly some other metabolite) in the lethality after MPTP injection. The reduced lethality of MPTP when given orally and the relative lack of brain levels of MPTP or MPP+ after oral MPTP implicate the brain as a target organ in the lethality of MPTP. Lethality after MPP+ administration almost certainly does not involve the brain, since little or no MPP+ could be measured in brain after oral or subcutaneous dosing of MPP+.
Fuller
R W
RW
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Hemrick-Luecke
S K
SK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007279:Injections, Subcutaneous; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D012642:Selegiline / Q000494:pharmacology; D014018:Tissue Distribution
D012642:Selegiline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium