Conversion of mitomycin C to 2,7-diaminomitosene and 10-decarbamoyl 2,7-diaminomitosene in tumour tissue in vivo.
The progress of mitomycin C (MMC) bioreduction was studied in vivo in the rat Sp 107 mammary carcinoma after intra-tumoural injection of either 100 micrograms or 1 mg. 2,7-Diaminomitosene (2,7-DM) was utilised as a primary bioreductive metabolite and 10-decarbamoyl 2,7-diaminomitosene (DC 2,7-DM) served as a secondary bioreductive metabolite, both of which were measured by high-performance liquid chromatography. 2,7-DM and DC 2,7-DM were produced rapidly, achieving close to their maximal concentrations at the earliest time point studied [5 min]. 2,7-DM was cleared rapidly from the tumour with apparent half-lives of 5 and 35 min after the low and high drug doses, respectively. DC 2,7-DM had a longer apparent half-life of 130 min at the higher dose but, as compared with 2,7-DM, was only a minor metabolite [the area under the curve (AUC) of 2,7-DM was 5.6-fold that of DC 2,7-DM]. At the lower drug dose, DC 2,7-DM was not detectable. Rapid formation and disappearance of bioreductive metabolites of MMC may account for the failure of previous studies to detect these products in vivo.
Chirrey
L
L
Department of Pharmacy, University of Strathclyde, Glasgow, UK.
Cummings
J
J
Halbert
G W
GW
Smyth
J F
JF
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism*; D016685:Mitomycin / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008937:Mitomycins / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains
D008937:Mitomycins; D016685:Mitomycin; C056707:2,7-diaminomitosene