4-Hydroxy cyclophosphamid

The clinical significance of the aforementioned findings is unknown. A report by Khakoo et al. (62) did not demonstrate a pharmacokinetic interaction between IFNa2i) and ribavirin or an additive effect of the combination therapy on safety assessments. In another study, administration of IFNa prior to the administration of cyclophosphamide significantly impaired the metabolism of cyclophosphamide and 4 hydrox-ycyclophosphamide. In contrast, the administration of IFNa after cyclophosphamide resulted in higher 4-hydroxy cyclophosphamide concentrations and produced a significant decrease in leukocyte count (63). 

Direct contact of the bladder epithelium with the catabolites acrolein and 4-hydroxy-cyclophosphamide is responsible for the hemorrhagic cystitis that can be a consequence of therapy with cyclophosphamide [78]. Aggressive hydration provides prophylaxis against this toxicity to the efferent urinary tract [79]. The sulfhydryl compound mesna has also demonstrated uroprotec-tive ability during therapy with cyclophosphamide [80]. Although hemorrhagic cystitis is a dose-related toxicity, chronic low doses of orally administered cyclophosphamide are also associated with development of this adverse event [81]. 

Cyclophosphamide Cardiac myocyte death 4-Hydroxy cyclophosphamid (metabolite) Altered ion homeostasis... 

Cyclophosphamide (36 R = H) is an effective agent for the treatment of many animal and human tumours and is oxidized in vivo by a mixed function oxidase of liver microsomes to produce a cytotoxic form of the drug. It was reported earlier that 4-hydroxy-cyclophosphamide (36 R = OH), a product of the oxidation of (36 R = H) with Fenton s reagent, was the... 

Figure 9.22 Release of chemotherapy drugs from polyanhydride matrices. Release of anticancer drugs from a pCPP/SA polyanhydride matrix, (a) BCNU, (b) 4-hydroxy-cyclophosphamide, and (c) paclitaxel. The insets in panels (a) and (b) show diffusion-controlled release (i.e., the percentage released is proportional with respect to the square root of time) is 7 x 10 and 3 x 10 ° cm /s, respectively. Data from [77].

Enzyme catalyzed oxidation of cyclophosphamide yields 4-hydroxy cyclophosphamide (e) and subsequent formation of aldophosphamide (f) that leads to phosphamide mustard (g) which is considered to be the ultimate alkylating agent. 

Cyclopent-2-en-l-one, 2-hydroxy-3-methyl-synthesis, 3, 693 Cyclopentenone, 4-methoxy-formation, 1, 423 Cyclopenthiazide as diuretic, 1, 174 Cyclopent[2,3-d]isoxazol-4-one structure, 6, 975 Cyclophane conformation, 2, 115 photoelectron spectroscopy, 2, 140 [2,2]Cyclophane conformation, 2, 115 Cyclophanes nomenclature, 1, 27 Cyclophosphamide as pharmaceutical, 1, 157 reviews, 1, 496 Cyclopiloselloidin synthesis, 3, 743 Cyclopolymerization heterocycle-forming, 1, 292-293 6H-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine pyrazoles from, 5, 285 Cydopropabenzopyran synthesis, 3, 700 Cyclopropachromenes synthesis, 3, 671 Cyclopropa[c]dnnolines synthesis, 7, 597 Cyclopropanation by carbenes... 

Ifosfamide (Ifex) is an analogue of cyclophosphamide that requires metabolic activation to form 4-hydroxy-ifosfamide. In general, the metabolism, serum half-life, and excretion of ifosfamide are similar to those of cyclophosphamide. 

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... 

Slott VL, Hales BF. 1988. Role of 4-hydroxy intermediate in the in vitro embryotoxicity of cyclophosphamide and dechlorocyclophosphamide. Toxicol Appl Pharmacol 92 170-178. 

Fig. 3 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-substrate anticancer agents. Abbreviations VCR vincristine, VP-16 etoposide, STER steroids, TAM tamoxiphen, TKI-INHIB tyrosin kinase inhibitors e.g. STI-571, DOX doxorubicine or adriamycin, DNR daunorubicin, EPIR epirubicin, MX mitoxantrone, TOPOT topotecan, iridotecan, BISANT bisanthrone, COLCH colchicin, ACT-D actinomycin D, MYTOM mytomycin, TX methotrexate, CPHAM cyclophosphamide, CHLB chlorambucil, CARM carmustine, LCV leucovorin, HUR hydroxy urea, CISPL cisplatin, TAXOL paclitaxel. (Reproduced from [4])...

Hassan M, Nilsson C, Olsson H, Lundin J, Osterborg A. The influence of interferon-alpha on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite in patients with multiple myeloma. Eur J Haematol 1999 63 163-70. 

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). ... 

Metabolism of the cytostatic drug cyclophosphamide (CP Fig. 1) involves hydroxylation at the C-4 position by cytochrome P450. Subsequently, a number of detoxification reactions can occur (oxidation to the keto derivative, dechloroethylation, formation of a carboxylic acid). The phosphoramide mustard resulting from spontaneous decomposition of 4-hydroxy-CP is thought to be the cytotoxic chemotherapeutic species. The chiral nature of the phosphorus atom resulted in a twofold greater therapeutic index (LDjq/EDjq) for the S-(-)-enantiomer (against the ADJ/PC6 plasma cell tumor in mice) without detectable differences in metabolism... 

Hassan M, Ljungman P, Ringden O, Hassan Z, Oberg G, Nilsson C, Bekassy A, Bielenstein M, Abdel-Rehim M, Georen S, Astner L. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant 2000 25(9) 915-24. 

A 26-year-old woman with a diffuse large B cell lymphoma received CHOP (cyclophosphamide, hydroxy-daunomycin, Oncovin, and prednisone), ritnximab, and radiotherapy (14). She developed a transfnsion-dependent anemia. Bone marrow biopsy confirmed pure red cell aplasia and parvovirus infection. She had no antibodies to parvovirus, suggesting that she never had a previous exposure. Intravenous immunoglobulin resulted in a reticulocytosis and recovery of her hemoglobin. 

In most species, cyclophosphamide is rapidly absorbed, metabolized, and excreted. In patients, cyclophosphamide was distributed rapidly to all tissues and exhibited a half-life of 6.5-7h. The majority of an administered dose (50-68%) was excreted in the urine and no parent compound or metabolite was detected in expired air or feces. Carboxyphosph-amide and phosphoramide mustard were detected in the urine. Cyclophosphamide is a racemer, and stereoselective metabolism by cytochrome P-450 of the enantiomers has been demonstrated in mice, rats, and rabbits. The primary metabolite is the 4-hydroxy derivative, and it exists in equilibrium with aldo-phosphamide, its ring-opened tautomer. Either metabolite can be converted by mammalian enzymes to 4-ketocyclophosphamide or to the propionic derivative. Both metabolites are relatively nontoxic and represent major urinary metabolites. 

The initial metabolism of cyclophosphamide is in the liver to the 4-hydroxy-derivative which is in equilibrium with the tautomeric aldehyde 33. It is proposed that selective anti-tumour action would result if normal cells could detoxify this metabolite by enzymatic conversion to known excretory products, the 4-keto or propionic acid derivatives 24 and 28. In the absence of such enzymes the metabolite is known to be unstable and to break down to acrolein 30 and phosphoramide mustard 31, both of which are very toxic to cells in culture66). Selective formation of these toxic breakdown products in tumours that have lost the appropriate detoxifying enzymes could obviously result in toxicity. 

Considerable interest is still being displayed in the synthesis of derivatives and analogues of cyclophosphamide (16). The 4-hydroperoxy-derivative (17), formed by ozonolysis of (16), may be deoxygenated by triphenylphosphine to the 4-hydroxy-derivative (18) (also formed by the hydrogenolysis of the 4-benzyloxy-com-pound ), which is reported to react with thiols to give the hydrosulphide (19). 

Sadagopan, N. Cohen, L. Roberts, B. Collard, W. Omer, C. Liquid Chromatography-Tandem Mass Spectrometric Quantitation of Cyclophosphamide and its Hydroxy Metabolite in Plasma and Tissue for Determination of Tissue Distribution," J. Chromatogr. B 159, 277-284 (2001). 

Patients with localized aggressive lymphomas can be cured with several cycles of cyclophosphamide, hydroxy-daunomycin (doxorubicin), vincristine (Oncovin), and prednisone (CHOP) chemotherapy and involved-field irradiation. Patients with bulky stage II, stage III, or stage IV aggressive lymphomas can be cured of their disease with CHOP chemotherapy. The addition of rituximab to CHOP (R-CHOP) is used by many centers in place of CHOP. 

The much used anticancer drug, cyclophosphamide 3.31) is inert until converted to the active agent by hepatic e.r. Some workers think that this active agent is the 4-hydroxy-derivative formed by metabolism (Takamizawa et al., 1975), but metabolism continues right down to the acyclic derivative (3.32), and this, or something in between, may be the true drug (Connors et al., 1974). 

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