Prodrugs cyclophosphamide

Kumar S, Chen CS, Waxman DJ, Halpert JR (2005) Directed evolution of manunalian cytochrome P450 2B1, mutations outside of the active site enhance the metabolism of several substrates, including the anticancer prodrugs cyclophosphamide and ifosfamide. J Biol Chem 280 19569-19575... 

CHOP Cyclophosphamide Alkylating agent Prodrug CYP 3A4/5, 2D6 Hemorrhagic cystitis... 

Amifostine (Elhyol) [Antineoplastic/Thiophosphate Cytoprotective] Uses Xerostomia prophylaxis during RT (head, neck, ovarian, NSCLQ -I- renal tox w/ rqjeated cisplatin Action Prodrug, dqjhosphorylated by alkaline phosphatase to active thiol metabohte Dose 910 mg/mVd 15-min IV inf 30 min prior to chemo Caution [C, +/—] CV Dz Disp Inj SE Transient X BP (>60%), NA, flushing w/ hot or cold chills, dizziness, X Ca % somnolence, sneezing Notes Does not -1- effectiveness of cyclophosphamide + cisplatin chemo Interactions T Effects W/ antih5 pertensives EMS Monitor BP for hypotension OD Severe hypotension treat w/IV fluids... 

Examples of GDEPT include irinotecan (CPT-11), a prodrug of 7-ethyl- 10-hydroxy-camptothecin activated by carboxylesterase 5-fluorocytosine, a prodrug of 5-FU activated by cytosine deaminase and cyclophosphamide, a prodrug of 4-hydroxycyclophosphamide activated by cytochrome P450, which degrades into acrolein and phospho-ramide mustard.112-115... 

Cyclophosphamide (Cytoxan, 8.104) is an anticancer prodrug that is oxidized by the C YP2B enzyme family in the liver (Scheme 8.27) and was first introduced back in Chapter 6. Oxidation occurs adjacent to the ring nitrogen to afford 4-hydroxycyclophosphamide (8.105), which is transported throughout the body by the circulatory system. Compound... 

Electrochemical oxidation of anticancer drugs ifosfamide and cyclophosphamide produced in high yield methoxylated analogues of the key hydroxy-metabolites of these oxazaphosphorine prodrugs (Scheme 19). ... 

Cytotoxic agents destroy immimologically competent cells. Azathioprine, a prodrug for the purine antagonist mercaptopurine, is used in autoimmune disease because it provides enhanced immunosuppressive activity. Cyclophosphamide is a second choice. Bone marrow is depressed as is to be expected. 

Cyclophosphamide is a prodrug which is converted into active metabolites in the liver. Urotoxic side effects must be anticipated they can be suppressed by the additional administration of sodium-2 mercaptoethanesulphonate. This alkylating substance has a strong immunosuppressive effect therefore, it is occasionally used to prevent graft rejection or (at a low dosage) in autoimmune hepatitis, (s. p. 686)... 

Cyclophosphamide is a prodrug that requires cjdochrome P450 -dependent hepatic activation to produce alkylating species and several inactive by-products. However, very few metabolic interactions involving cyclophosphamide have been reported. In a retrospective study of 22 children treated with cyclophosphamide for cancer or bone marrow transplantation, cyclophosphamide clearance was significantly lower in nine patients taking fluconazole compared with 13 patients not taking it (77). In vitro studies in human hver microsomes confirmed that the rate of 4-hydroxylation of cyclophosphamide was inhibited by fluconazole. 

Cyclophosphamide is a prodrug that is metabolized by CYP450 enzymes to produce alkylating species, which are cytotoxic, and the extent of cyclophosphamide metabolism correlates with both treatment efficacy and toxicity. In vitro studies in six human liver microsomes showed that the IC50 of fluconazole for reduction of 4-hydroxycyclo-phosphamide production was 9-80 pmol/1 (93). 

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. 

Phosphoramide mustard is the proven cytotoxic metabolite of cyclophosphamide, a successful clinical anticancer prodrug that requires cytochrome P450 activation in the liver. These nitroaryl phosphoramides in combination with nitroreductase could effectively move the site of activation from liver in the case... 

All prodrugs are stable in aqueous buffer but undergo A -demethylation when incubated with rat hepatic micro-somes, forming alkylating species. Ai-Methyl-4-(diethyl-dithiocarbamyl) cyclophosphamide particularly (Figure 41.6) shows notable in vitro toxicity against mouse 3T3 cells and human tumor cells. 

Although many alkylating agents are administered in the active form, cyclophosphamide (14) is a prodrug activated in the liver. 

The presence of an alkyl substituent at N3 in the oxazaphosphorine ring stabilizes Af-substituted 4-(alkylthio)cyclophosphamides from spontaneous decomposition. On the basis of this finding, several Ai-methyl-4-thiocyclophosphamide derivatives were synthesized and examined as prodrugs of 4-hydroxycyclophos-phamide, the activated species of cyclophosphamide. ... 

Two chiral drugs commonly used in the treatment of cancer are the alkylating agents cyclophosphamide and ifosfamide (Fig. 2). From a chemical perspective, both drugs are distinctive in that their chiral centers are phosphorous rather than carbon atoms. Another feature common to both drugs is that they are really prodrugs, as pharmacological action is attributable to metabolites formed by a specific pathway. 

Cyclophosphamide is closely related in its mode of action to the nitrogen mustards. It is a prodrug which is activated via the action of a P450 enzyme as shown in Figure 21.4. 

---