1. The metabolism of the radiosensitizing 2-nitroimidazole, misonidazole, has been investigated in mice, rats, baboons, human volunteers, and in patients receiving radiotherapy for advanced malignant disease. 2. Plasma levels of unchanged drug and its desmethylated metabolite have been measured, and in humans there is good correlation of peak plasma concn. with drug dose. All drug-related material in plasma was accounted for as unchanged misonidazole or its desmethylated metabolite, both compounds being radiosensitizers in vitro. 3. Extensive faecal excretion of material not containing any nitro group occurred in mice, rats, and baboons dosed with radiolabelled drug. 4. Renal excretion is the preferred route of elimination in man, baboon and mouse. Nitroimidazole metabolites accounting for over half the urinary excretion in all species were identified. 5. The compound penetrates solid murine tumours in concentrations sufficient to achieve radiosensitization.
I The urinary recovery and plasma concentration of debrisoquine (D) and its metabolite 4-hydroxydebrisoquine (HD) has been studied following single and multiple oral administration of debrisoquine hemisulphate to 15 hypertensive in-patients and four normal volunteers. The distribution of D in the blood was studied after a single dose to one volunteer. The greatest concentration of the drug was in the platelet rich fraction from which it was eliminated slowly. The elimination half-lives in plasma and platelet rich plasma were 17.5 h and 56 h respectively. 7 On early multiple dosing the hypotensive response was related to high plasma D concentrations.
weeks (P< 0-01) in those who responded well and by six weeks (P<005) in those who showed no remission. Among patients with normal prolactin values the release of prolactin after thyrotrophin-releasing hormone was significantly greater in those with no remission than in those who responded to tamoxifen. Responses in those with hyperprolactinaemia were reduced to about half the control values, and again this change occurred faster in those who were successfully treated. Patients therefore seem to have a better chance of responding to antioestrogen treatment if prolactin secretion is low.
1. The metabolism of debrisoquine sulphate in the dog has been studied and is similar to that in rat and man. 2. Two acidic urinary metabolites, shown to be present in rat, dog and man, have been isolated from rat urine. After derivatization they were characterized by n.m.r. and mass spectroscopy as methyl 2-[2-(4,6-dimethylpyrimidylamino)-methyl]-phenylacetate and 2-[2-(4,6-dimethylpyrimidylamino)-ethyl]benzoate.
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