Disease relevance of 4-OH-CP

• Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients [1].
• Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is decreased by the protector thiol L-cystein [2].
• The pharmacokinetics of cyclophosphamide (CP) and its cytotoxic metabolite 4-hydroxycyclophosphamide (4-OHCP) have been studied in multiple myeloma patients treated with the CIB (CP, interferon-alpha (IFN-alpha) and betamethasone) regimen [3].
• It is concluded that 4-hydroxycyclophosphamide interferes with the charging process of tRNALeu in E. coli leading to an inhibition of protein synthesis [4].
• One of the 4-(S-R)-mercapto-cyclophosphamide compounds was tested biologically in vitro against Yoshida ascites tumor cells and showed the same cytotoxic activity as 4-hydroxycyclophosphamide [5].

High impact information on 4-OH-CP

• However, the effect on AUC for the major oncolytic metabolites 4-hydroxycyclophosphamide and phosphoramide mustard was not statistically significant [6].
• We have investigated the formation of 4-hydroxycyclophosphamide (HCY) and deschloroethylcyclophosphamide (DCCY) from cyclophosphamide (CY) in human liver microsomes [7].
• Cyclophosphamide, a widely used anticancer agent, requires initial metabolic activation to 4-hydroxycyclophosphamide (4-OHCP) to elicit its activity [8].
• Three established human colon carcinoma cell lines (LoVo, SW620, and SW403) with different degrees of phenotype differentiation were investigated for their sensitivity to the cytotoxic effects of cyclophosphamide (CP) and to its active metabolite, 4-hydroxycyclophosphamide (4-OH-CP), and for their mixed function oxidase (MFO) activities [9].
• The rates at which the 4-hydroxyoxazaphosphorines, 4-hydroxycyclophosphamide and 4-hydroxyifosfamide, are converted to reactive mustards and acrolein in phosphate and bicarbonate buffers were determined as a function of pH, ionic strength, temperature, and buffer concentration [10].

Chemical compound and disease context of 4-OH-CP

• AIMS: This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation [11].
• According to this hypothesis, toxicity and canceroselectivity are the results of phosphoramide mustard (PAM) release from 4-OH-CP catalysed by two classes of phosphodiesterase [12].
• Because high AUCs of 4-hydroxycyclophosphamide, thiotepa/tepa and carboplatin correlate with increased toxicity, the treatment risk in this obese patient was significantly increased [13].

Biological context of 4-OH-CP

• Inhibition of neutrophil chemotaxis by 4-hydroxycyclophosphamide [14].
• OBJECTIVES: To characterize the pharmacokinetics of cyclophosphamide and 5 of its metabolites in bone marrow transplant patients and to identify the mechanism of the increase in 4-hydroxycyclophosphamide area under the plasma concentration-time curve (AUC) from day 1 to day 2 of cyclophosphamide administration [15].
• For those analogues that could undergo cyclization, this pathway competed effectively with enamine release, and these analogues were essentially equivalent to their 4-hydroxycyclophosphamide counterparts in cytotoxicity [16].
• In murine dermal endothelial cells (F-2), 4-hydroxycyclophosphamide (4-HC), which is active metabolite of CPA, enhanced TNF-alpha-induced DNA fragmentation [17].
• Cycloheximide or ZnSO4 did not suppress 4-OH-CP induced apoptosis [18].

Anatomical context of 4-OH-CP

• 4-hydroxycyclophosphamide (4HCy) inhibits T cell-dependent and direct B cell humoral responses of human lymphocytes in vitro, but causes a potentiation of the former in the lowest drug concentrations [19].
• After preincubation of microsomes with 0.2 mM 4-hydroperoxycyclophosphamide, a prodrug of 4-hydroxycyclophosphamide, there was complete denaturation of the cytochrome P-450, and 22.8% inhibition of NADPH-cytochrome P-450 reductase [20].
• There is increasing recognition of the importance of the erythrocyte as a carrier of compounds in the circulation, and we have recently described higher concentrations of 4-hydroxycyclophosphamide within the erythrocyte compartment compared to plasma [21].
• Etoposide, a topoisomerase II inhibitor known to induce apoptosis in human tumor cell lines like 4-OH-CP, did induce detectable DNA fragmentation in only a minor proportion of T-lymphocytes but suppressed T-cell proliferation [18].

Associations of 4-OH-CP with other chemical compounds

• We conclude that, in the reaction sequence 4-hydroxycyclophosphamide leads to aldophosphamide leads to phosphoramide mustard + acrolein, the conversion of 4-hydroxycyclophosphamide to aldophosphamide is rate limiting and is subject to bifunctional catalysis; this reaction can proceed efficiently only in the presence of a bifunctional catalyst [22].
• Conversion of 4-hydroperoxycyclophosphamide to 4-hydroxycyclophosphamide in 0.5 M Tris buffer, pH 7.4, 37 degrees, was first-order (k = 0.016 min-1), but subsequent conversion of 4-hydroxycyclophosphamide to phosphoramide mustard and acrolein under these conditions was negligible [22].
• Population pharmacokinetics of cyclophosphamide and its metabolites 4-hydroxycyclophosphamide, 2-dechloroethylcyclophosphamide, and phosphoramide mustard in a high-dose combination with Thiotepa and Carboplatin [23].
• One procedure in which a fluorescent hydroxyquinoline derivative was prepared from 4-hydroxycyclophosphamide and analyzed by HPLC appeared to work at first, but gradually lost its selectivity due to degradation of the column by the strongly acidic mobile phase [24].
• This goal is facilitated by the rapid transfer of 4-OH-CP released from the perhyrothiazine derivative NSC 612567 to protein SH groups, as shown by protein-binding studies [12].

Gene context of 4-OH-CP

• CYP2B6 also manifested a strong 4-hydroxycyclophosphamide activity [25].
• 1. However, in liver microsomes, there were no statistically significant differences in the intrinsic clearance of 4-hydroxycyclophosphamide formation between the group of seven CYP2C9*1/*1 livers and the remaining nine with one or two variant CYP2C9 alleles ( P>0.7) [26].
• The formation of 4-hydroxycyclophosphamide was studied in microsomes from a total of 32 different genotyped human livers, as well as in yeast microsomes expressing different genetic variants of CYP2C9 and CYP2C19 [26].
• Increased MRP was also associated with modest resistance to the oxazaphosphorine compounds mafosfamide, 4-hydroxycyclophosphamide, and 4-hydroperoxycyclophosphamide [27].
• OBJECTIVES: Our objectives were (1) to develop a population pharmacokinetic model for cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide mustard (a reporter for nonrelapse mortality) in hematopoietic stem cell transplantation patients and (2) to validate a Bayesian approach to dosing [28].

Analytical, diagnostic and therapeutic context of 4-OH-CP

• A liquid chromatography method including liquid-liquid extraction and protein precipitation in one step was developed to measure 4-hydroxycyclophosphamide in plasma [29].
• Previously reported methods for determining 4-hydroxycyclophosphamide were either impractical or unreliable for monitoring infusion pharmacokinetics in conjunction with clinical trials [24].
• In addition, in rats receiving prodrug cyclophosphamide (CP), plasma concentrations of CP and its metabolites, 4-hydroxycyclophosphamide (HOCP), PM, and CEA, were simultaneously quantified using GC/MS and stable isotope dilution techniques [30].
• Concentrations of cyclophosphamide, 4-hydroxycyclophosphamide, 4-ketocyclophosphamide and 2-dechloroethylcyclophosphamide were determined in plasma, liver and tumour tissue using coupled high-performance liquid chromatography-mass spectrometry at different times after treatment [31].

References