Development Pharmacology

The effect of methyltyrosine methylester (H 44/68) on the brain levels of noradrenaline (NA) and dopamine (DA) 16 hours after the administration in adult and in developing mice aged 3‐5 days and 13‐15 days was studied. In the youngest mice 250 mg/kg of H 44/68 markedly decreased the brain catechol‐amines (CA), whereas in 13‐15‐day‐old mice even 500 mg/kg of H 44/68 failed to reduce the DA level. After this dose NA was decreased to 25%. In adult brains both doses of H 44/68 caused pronounced reduction of the CA levels, DA decreasing more than NA. High doses of amphetamine (50‐120 mg/kg) given to H 44/68‐pretreated mice were less toxic than without pre‐treatment. Amphetamine generally enhanced the H 44/68‐induced depletion of brain CA, except in the youngest mice, in which amphetamine (120 mg/kg) counteracted the brain DA depletion induced by H 44/68. It is suggested that the varying changes in the CA levels in H 44/68‐treated developing mice might result from differences in the turnover rates of CA during development. Enhancement by amphetamine of H 44/68‐induced reduction in CA reflects the accelerating effect of amphetamine on CA metabolism.

Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Modification by Methyltyrosine Methylester (H 44/68) of the Amphetamine‐Induced Toxicity and Brain Catecholamine Changes in Developing Mice

Alhava

1973

“…This reflects a high hydrolytic activity in this age group and is in agreement with the Ifindings of DONE (1964), who mentioned that the hydrolytic reactions of developing animals occur as actively as those of mature animals. In this respect the infant mice lie between adult and 13-15-day-old mice, which might indicate a relative immaturity of the general metabolic processes in very young animals (DONE 1964;MIRKIN 1970). The hypokinesia seen after the administration of H 19/61 in adult and developing mice tallies with the finding of STROMBERG (1970), who revealed a dose-dependent reduction in motor activity in mice injected with L-DOPA in a dose range of 31.3 to 250 mg/kg.…”

Section: Discussionmentioning

confidence: 99%

Modification by L‐DOPA Methylester (H 19/61) of Amphetamine‐Induced Brain Catecholamine Changes, Thermal Responses and Toxicity in Developing Mice

Alhava

1973

The effect of 150 mg/kg of L‐DOPA methylester on brain catecholamines was studied in adult and developing mice aged 3‐5 days and 13‐15 days. Noradrenaline was moderately increased in the developing brain but dopamine showed a manyfold increase. The increase of dopamine was less pronounced in adult brain. High doses of dl‐amphetamine (50‐160 mg/kg) injected to L‐DOPA pretreated mice further increased the dopamine levels in the developing brain. The adult brain catecholamines were remarkably depleted, provided the observation period was 4 hours after amphetamine. Amphetamine lowered the body temperature in mice aged 13‐15 days; the fall was dose‐dependent and potentiated by pretreatment with L‐DOPA. In adult mice amphetamine caused hyperthermia which was not modified by L‐DOPA. L‐DOPA did not change the mortality rates induced by amphetamine in developing mice, but infant mice pretreated with L‐DOPA showed a lower brain amphetamine concentration after death than the mice given amphetamine only. In adult mice GDOPA enhanced amphetamine toxicity. Special attention is paid to the importance of different turnover rates of catecholamines during development as well as to the complex action of amphetamine on enzymes regulating catecholamine turnover. It is assumed that the hypothermia of developing mice after amphetamine might result from the primary effect of amphetamine on dopaminergic mechanisms.

“…In most previous reviews on drug metabolism the main emphasis has been given to the foetal and postnatal development of drug hydroxylation reactions (MIRKIN 1970;YAFFE & RANE 1971;RANE & SJOQVIST 1972;PELKONEN 1973b) or to the enhancement of drug hydroxylation after an administration of various compounds (CONNEY 1967(CONNEY & 1972KUNTZMAN 1969;GELBOIN 1971). The later phases of life and the synthetic detoxification reactions have received less attention.…”

mentioning

confidence: 99%

Age and Exposure Factors in Drug Metabolism

Hänninen

1975

The development of drug metabolism in the foetal and postnatal periods varies in different species. It is also different in different tissues. The capacity of tissues to catalyze drug hydrolysis, oxidation and reduction as well as the conjugation reactions appears to mature in different phases. The human foetus seems to be better equipped than the foetuses of other species, since both drug hydroxylation and e.g. salicyluric acid synthesis take place sooner than in other species. Glucuronide synthesis can also be detected early in human foetal tissues. During adulthood the drug metabolism decreases with age at least in the rat. The exposure of the organism to foreign compounds often results in an increase in the rate of drug metabolism. This can also be detected in foetal tissues. In the liver similar responses to successive exposures to inducing chemicals can be found at least in the young adult rats, providing they have had sufficient time to recover from previous loadings. In old rats the drug metabolizing enzymes are poorly induced. The diseased state of organs responsible for the detoxication reactions show a lower capacity to handle drugs. The mucosal cells of the intestine serve as a special model for studies on drug biotransformation, since their life span is short and cells at different developmental phases are available at the same time.