Medicinal azides. Part 3. The metabolism of the investigational antitumour agent meta-azidopyrimethamine in mouse tissue in vitro.
1. The experimental antitumour agent meta-azidopyrimethamine is deactivated by reduction of the azide moiety to yield meta-aminopyrimethamine. This reaction was followed by h.p.l.c. subsequent to incubation of the drug with homogenates prepared from liver, kidney, spleen, intestine and heart of mice. Reducing activity was highest in liver homogenate and was time dependent. Following the incubation of 530 nmol meta-azidopyrimethamine with liver homogenate equivalent to 1 g liver for 30 min under air, 84% of the agent was reduced to meta-aminopyrimethamine. 2. Reducing activity was markedly lower in incubations containing subcellular fractions obtained from liver homogenate. Under aerobic conditions the 700 g and 12,500 g supernatant fractions were able to reduce 57% and 23%, respectively, of the amount of meta-azidopyrimethamine initially present. The respective pellets possessed weak reducing ability, but on reconstitution of the supernatants with their corresponding pellets most of the reducing activity as observed in the whole homogenate was recovered. 3. Microsomes and mitochondria reduced the drug only when incubations were performed in the presence of nitrogen but not under air. 4. A fraction of the reducing activity measured in the tissue homogenates was non-enzymatic, as heat-inactivated homogenates retained less than 10% of the activity exhibited by the untreated homogenates. Neither bovine serum albumin nor glutathione could reduce meta-azidopyrimethamine under the conditions of the tissue incubations, whereas dithiothreitol was a powerful reductant. The mixed enzymatic and non-enzymatic nature, the tissue distribution and the diffuse subcellular localisation of meta-azidopyrimethamine reducing activity resemble features of the bioreduction of N-oxides.
Kamali
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F
Cancer Research Campaign Experimental Chemotherapy Research Group, Birmingham, U.K.
Gescher
A
A
Slack
J A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001386:Azides / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D011739:Pyrimethamine / Q000031:analogs & derivatives*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D013347:Subcellular Fractions / Q000378:metabolism
D000970:Antineoplastic Agents; D001386:Azides; D011743:Pyrimidines; C055910:3-azidopyrimethamine; D011739:Pyrimethamine