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Metabolism of n methyl containing anti tumor agents carbon 14 di oxide breath analysis after administration of carbon 14 labeled n methyl drugs formaldehyde and formate in mice

Metabolism of n methyl containing anti tumor agents carbon 14 di oxide breath analysis after administration of carbon 14 labeled n methyl drugs formaldehyde and formate in mice

Biochemical Pharmacology 30(11): 1245-1252

The 14CO2 content of the breath was analyzed after administration of the following N-14CH3 labeled drugs to mice: aminopyrine, hexamethylmelamine (HMM), pentamethylmelamine (PMM), procarbazine and caffeine. Except for aminopyrine, the 14CO2 exhalation rate plots declined monophasically with half lives [t1/2] of 91 min ([14C]-HMM), 97 min ([14C]-PMM), 68 min ([14C]procarbazine) and 92 min ([14C]caffeine). The 14CO2 exhalation rate peaked rapidly after aminopyrine administration and declined bi-phasically with an initial t1/2 of 15 min and a terminal t1/2 of 126 min. The 14CO2 plots after both [14C]-HMM and [14C]amiopyrine were influenced by pre-treatment of mice with proadifen. Pretreatment with phenobarbitone shortened the t1/2 of the 14CO2 appearance rate after [14C]HMM by 24% but did not change the 14CO2 curve after administration of [14C]aminopyrine. The 14CO2 exhalation rate plots after administration of H14CHO and H14COOH were virtually identical with that obtained after [14C]aminopyrine and not influenced by either proadifen or phenobarbitone pretreatment. The 14CO2 exhalation rate profile obtained on metabolism of [14C]aminopyrine in mice thus appears to be determined by the rate of the oxidation of formaldehyde or formate to CO2. Only 24% of the label injected with the N-methyl moieties of [14C]HMM and 21% of the label in [14C]procarbazine were exhaled as 14CO2; 49% of the N-14CH3 in [14C]aminopyrine were metabolized to 14CO2. It remains to be determined whether this difference and the difference in the shapes of the 14CO2 exhalation profiles obtained with the cytotoxic N-14CH3 drugs as compared to [14C]aminopyrine, are related to the biochemical processes mediating their antineoplastic activity.

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Accession: 005884634

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