Bioactivation cyclophosphamide

Fantel AG, Greenaway JC, Juchau MR, Shepard TH (1979) Teratogenic bioactivation of cyclophosphamide in vitro. Life Sci, 25 67-72. 

Figure 34.5. Metabolic pathway for the bioactivation of cyclophosphamide. (Adapted from Mirkes,P. E. Cyclophosphamide teratogenesis A review. Teratog. Carcinog. Mutagen. 5,75-88, 1985.)...

In general, drug metabolism serves to inactivate a substrate and increase water solubility of the substrate for excretion, bioactivate a substrate or prodrug (e.g., codeine and cyclophosphamide) to an active or mutagenic principle, or less commonly, extend the elimination half-life of a pharmacologically active or potentially toxic metabohte. Metabolic reactions are often divided into Phase I and Phase II categories, as depicted in Figure 43-1. 

Answer A. The symptoms are those of a mild case of hemorrhagic cystitis. Bladder irritation with hematuria is a fairly common complaint of patients treated with cyclophosphamide, It appears to be due to acrolein, a product formed when cyclophosphamide is bioactivated by liver P450 to form cytotoxic metabolites. Urinary tract problems may also occur with methotrexate from crystalluria due to its low water solubility. 

F Bioactivation of cyclophosphamide Reductive Bioactivations A Reductive bioactivation of nitrogen mustards... 

Bioactivation to a free radical intermediate has been implicated in the teratological mechanism for a number of xenobiotics, including phenytoin and structurally-related AEDs, benzo[a]pyrene, thalidomide, methamphetamine, valproic acid, and cyclophosphamide (Fantel 1996 Wells et al. 2009 Wells and Winn 1996). Unlike in the case of most CYPs, the embryo-fetus has relatively high activities of PHSs and lipoxygenases (LPOs), which via intrinsic or associated hydroperoxidase activity can oxidize xenobiotics to free radical intermediates (Fig. 10) (Wells et al. 2009). These xenobiotic free radical intermediates can in some cases react with double bonds in cellular macromolecules to form covalent adducts, or more often react directly or indirectly with molecular oxygen to initiate the formation of potentially teratogenic reactive oxygen species (ROS). 

Huitema ADR, Kerbusch T, Tibben MM, Rodenhuis S, Beijnen JH. Reduction of cyclophosphamide bioactivation by thioTEPA critical sequence-dependency in high-dose chemother y regimens. Cancer Chemother Pharmacol 2( 0) 46,119-27. 

Yang, J. and Du, Y. Chemical modification, characterization and bioactivity of Chinese lacquer polysaccharides from lac tree Rhus vernicifera against leukopenia induced by cyclophosphamide. Carbohydr... 

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