Cyclophosphamide metabolism

Berrigan MJ, Gurtoo HL, Sharma SD, et al. 1980. Protection by N- acetylcystein of cyclophosphamide metabolism-related in vivo depression of mixed function oxygenase activity and in vitro denaturation of cytochrome P-450. Biochem Biophys Res Commun 93 797-803. 

Sladek NE. 1973. Cyclophosphamide metabolism. 5. Bioassay and relative cytotoxic potency of cyclophosphamide metabolites generated in vitro and in vivo. Cancer Res 33 1150-1158. 

Rae JM, Soukhova NV, Flockhart DA, Desta Z (2002) Tri-ethylenethiophosphoramide is a specific inhibitor of cytochrome P450 2B6 implications for cyclophosphamide metabolism. Drug Metab Dispos 30(5) 525-530 Riley R, Howbrook D (1997) In vitro analysis of the activity of the major human hepatic CYP enzyme (CYP3A4) using [N-methyl-14C]-erythromycin. J Pharmacol Toxicol Methods 38(4) 189-193... 

CYCLOPHOSPHAMIDE H2 RECEPTOR BLOCKERS-CIMETIDINE t adverse effects of alkylating agent, e.g. myelosuppression 1. Additive toxicity 2. Possible minor inhibition of cyclophosphamide metabolism via CYP2C9 Avoid co-administration of cimetidine with cyclophosphamide... 

Yule SM, Walker D, Cole M, McSorley L, Cholerton S, Daly AK, Pearson AD, Boddy AV. The effect of fluconazole on cyclophosphamide metabolism in children. Drug Metab Dispos 1999 27(3) 417-21. 

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). 

A retrospective study in 22 children with cancers addressed the potential interaction between fluconazole and cyclophosphamide. Children with an established profile of cyclophosphamide metabolism who were not receiving other drugs known to affect drug metabolism were selected 9 were taking fluconazole and 13 were controls. The plasma clearance was significantly lower in patients taking concomitant fluconazole (2.4 versus 4.2 1/ hour/m ). It is unclear whether this interaction is associated with a reduction in the therapeutic efficacy of cyclophosphamide. 

Figure 4-9. Cyclophosphamide metabolism and activation (proposed by Connors et al., 1974).

Rae J.M., N.V Soukhova, D.A. Flockhart, and Z. Desta (2002). Triethylenethiophosphoramide is a specific inhibitor of cytochrome P4502B6 Implications for cyclophosphamide metabolism. Drug Metab. Dispos. 30, 525-530. 

As effective as mesna is for preventing acrolein-induced urotoxicity, it does little to spare the kidney and nerve cells from chloroacetaldehyde, the other toxic by-product of cyclophosphamide metabolism (18). Luckily, only approximately 10% of a standard dose of cyclophosphamide undergoes the dechloroethylation reaction, although this percentage can rise if higher doses are used (16). 

Marr KA, Leisenring W, Crippa F, Slattery JT, Corey L, Boeckh M, McDonald GB. Cyclophosphamide metabolism is affected by azole antifungals. Blood (2004) 103,1557-9. 

Williams ML, Wainer IW, Embree L, BarnettGranvil CL, Ducharme MP. Enantioselective induction of cyclophosphamide metabolism by phenytoin. Chirality (1999) 11, 569-74. 

In an early study, single doses of prednisone were shown to inhibit the metaholie aetivation of cyclophosphamide, whereas another study briefly mentioned that massive single doses of prednisolone given just before eyelophosphamide did not inhibit cyclophosphamide metabolism. Longer-term prednisone treatment (50 mg daily for 1 to 2 weeks) increased the rate of aetivation of cyclophosphamide in the first study. Conversely, another study in 7 patients with systemic vasculitis given prednisone 1 mg/kg daily and cyclophosphamide 600 mg/m intravenously every 3 weeks for 6 eyeles found that, by the last cycle, the AUC of cyclophosphamide had significantly increased while that of its active metabolites had significantly decreased. ... 

Yu LJ, Drewes P, Gustafsson K, Brain EGC, Hecht JED, Waxman DJ. In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism impact on pharmacokinetics and antitumor ctmty.JPhamacolExp Ther( 999) 288, 928-37. 

Helsby N, Tingle M (2011) The importance of correct assignment of CYP2B6 genetic variants with respect to cyclophosphamide metabolizer status. Am J Hematol 86 383-384... 

Yao S, Barlow WE, Albain KS, Choi JY, Zhao H, Livingston RB, Davis W, Rae JM, Yeh IT, Hutchins LF, Ravdin PM, Martino S, Lyss AP, Osborne CK, Abeloff M, Hortobagyi GN, Hayes DF, Ambrosone CB. Gene polymorphisms in cyclophosphamide metabolism pathway, treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer. Clin Cancer Res 2010 16(24) 6169-76. 

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