Dose-dependent pharmacokinetics of alpha-methyl-p-tyrosine (alpha-MT) and comparison of catecholamine turnover rates after two doses of alpha-MT.
Groups of rats were injected i.p. with 0.407 or 1.02 mmoles/kg of D,L-alpha-methyl-p-tyrosine methylester HCl (alpha-MT). The time-courses for alpha-MT in plasma and brain were followed together with the endogenous brain dopamine (DA) and noradrenaline (NA) contents. The elimination of alpha-MT from plasma and brain was markedly delayed after the high alpha-MT dose compared with the low dose. At 40 hours after the injection of 1.02 mmoles/kg of alpha-MT both plasma and brain levels were high, whereas no alpha-MT could be detected in plasma or brain at 16 hours after the lower dose. The brain catecholamines were decreased to very low values after the higher alpha-MT dose (DA 14% and NA 10% of controls at 8 and 24 hours respectively). There was no complete recuperation at 40 hours of any of the amines. After the lower alpha-MT dose, the DA concentration was back to control levels at 16 hours and NA at 12 hours. Between 16--40 hours after the high alpha-MT dose a majority of the rats showed prominent signs of sedation, weight loss and dehydration. No such signs were observed in rats receiving 0.407 mmoles/kg. During the first hour after the alpha-MT injection the declines of DA and NA respectively were almost identical for both alpha-MT doses. When the whole time-course (0--8 hours) after the high dose was considered, biphasic declines were obtained for both DA and NA, suggesting at least two different catecholamine pools. However, due to toxic effects after the high alpha-MT dose, turnover data have to be interpreted with caution.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D008781:Methyltyrosines / Q000378:metabolism / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats
D008781:Methyltyrosines; D004298:Dopamine; D009638:Norepinephrine