Pharmacokinetics of (R)- and (S)-cyclophosphamide and their dechloroethylated metabolites in cancer patients

Williams, Monique; Wainer, Irving W.; Granvil, Camille; Gehrcke, Bärbel; Bernstein, Mark L.; Ducharme, Murray P.

doi:10.1002/(sici)1520-636x(1999)11:4<301::aid-chir7>3.0.co;2-r

Cited by 27 publications

(29 citation statements)

References 10 publications

(23 reference statements)

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“…1) is a chiral drug widely used in cancer and immunosuppressive therapy, which is administered as a racemic mixture of its two enantiomers, (1)-(R)-CPA and (2)-(S)-CPA. 1 (2)-(S)-CPA is considerably more effective (lower ID 90 ) in killing tumor cells than (1)-(R)-CPA. 2 CPA is primarily converted by liver cytochrome P450 enzymes into 4-hydroxycyclophosphamide (4-OHCPA), an active metabolite.…”

Section: Introductionmentioning

confidence: 99%

“…4 Despite the vast number of clinical pharmacokinetic reports on CPA, few studies have investigated the stereo- selectivity in the kinetic disposition and metabolism of CPA. 1,[5][6][7][8][9] It has been suggested that (1)-(R) and (2)-(S)-CPA may differ in their therapeutic and toxic effects, but the clinical consequences of these differences have not been adequately determined. 1 Many chromatography-based analytical techniques have been used to measure CPA as enantiomeric mixture in human plasma, including high-performance liquid chromatography with ultraviolet detection (HPLC-UV), gas chromatography-nitrogen phosphorus detection (GC-NPD), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and thinlayer chromatography (TLC)-photography densitometry.…”

Section: Introductionmentioning

confidence: 99%

“…The resulting diastereomeric pair was resolved on a Hypersil 1 ODS column and detected by UV with an analytical run time of 25 min. Williams et al 1 reported the determination of CPA enantiomers in human plasma and urine by GC-MS using a capillary column coated with a chiral stationary phase composed of heptakis (6-…”

Section: Introductionmentioning

confidence: 99%

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Determination of cyclophosphamide enantiomers in plasma by LC‐MS/MS: Application to pharmacokinetics in breast cancer and lupus nephritis patients

et al. 2008

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This article describes the enantioselective analysis of cyclophosphamide (CPA) in human plasma using LC-MS/MS. CPA enantiomers were extracted from plasma using a mixture of ethyl acetate and chloroform (75:25, v/v). The enantiomers were separated on a Chiralcel(R) OD-R column, with the mobile phase consisting of a mixture of acetonitrile and water (75:25, v/v) plus 0.2% formic acid. The protonated ions and their respective product ions were monitored using two functions, 261 > 141 for CPA enantiomers and 189 > 104 for the internal standard (antipyrine). Recovery rates were higher than 95% and the quantification limit was 2.5-ng/ml plasma for both enantiomers. The coefficients of variation and the relative errors obtained for the validation of intra- and interassay precision and accuracy were less than 10%. The method was applied for the investigation of the enantioselective pharmacokinetics of CPA in a lupus nephritis patient treated with 1 g CPA infused over 2 h and in a breast cancer patient treated with 0.9 g infused over 1 h. No stereoselectivity in the pharmacokinetic parameters was observed for either patient. Clearance values of 2.63 and 2.93 l/h and of 3.36 and 3.61 l/h for (-)-(S) and (+)-(R)-CPA were obtained for the breast cancer and lupus nephritis patient, respectively.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Determination of cyclophosphamide enantiomers in plasma by LC‐MS/MS: Application to pharmacokinetics in breast cancer and lupus nephritis patients

et al. 2008

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“…Organophosphorus chemistry 1 is a very active research field that concerns numerous applications in agrochemistry, 2 health, 3,4 biology, 5 materials 6 and additives, 7 hydrometallurgy, 8 … Chiral organophosphorus compounds are also of particular interest because their properties often depend on their configuration. [2][3][4][5] Indeed, they played a significant role as ligands in metal based asymmetric catalysis 9 as well as Brönsted acid or Lewis bases in organocatalysis.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4][5] Indeed, they played a significant role as ligands in metal based asymmetric catalysis 9 as well as Brönsted acid or Lewis bases in organocatalysis. 10 Usually, the stereoselective synthesis of chiral organophosphorus compounds with P-C bond formation was performed using chlorophosphines or phosphides as electrophilic or nucleophilic reagents, respectively.…”

Section: Introductionmentioning

confidence: 99%

P-Chirogenic silylphosphine-boranes: synthesis and phospha-Michael reactions

Bonnefille¹,

Tessier²,

Cattey³

et al. 2015

Arkivoc

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Chiral and achiral silylphosphine-boranes were prepared in high yields by reaction of phosphide boranes with halogenosilanes. Their reaction at room temperature with Michael acceptors afforded 1,4-addition products as silylenol ether or ketone derivatives in good to excellent yields. In the case of the 2,3-dihalogeno-maleimides, the double addition of silylphosphine-borane led to the corresponding trans-diphosphine-boranes in 86% yield. Noteworthy, the reaction of Pchirogenic silylphosphine-boranes with enones afforded the phospha-Michael adducts without racemization at the P-center. While the silylphosphine-boranes have been scarcely described so far, these compounds demonstrate their great interest for the synthesis of chiral and achiral functionalized organophosphorus compounds.

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Enantioselective induction of cyclophosphamide metabolism by phenytoin

et al. 1999

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The objective of this study was to investigate the effect of phenytoin (PHE) on cyclophosphamide (CP) disposition. CP was administered to 6 adult patients in a preparative regimen for bone marrow transplantation consisting of busulfan and CP. Three of the patients received PHE and the other 3 “control” patients received diazepam (DZP) as anti‐epileptic prophylactic treatment. Plasma samples were collected at intervals up to 24 h after CP administration. The plasma concentrations of (R)‐ and (S)‐CP and their respective N‐dechloroethylated metabolites, (R)‐ and (S)‐DCE‐CP were simultaneously fitted using an enantiospecific 2‐compartment pharmacokinetic (PK) model with Bayesian control estimation. DZP had no significant effect on the metabolism of CP and any of its PK parameters. PHE, however, increased significantly the formation of (S)‐DCE‐CP while having no effect on the formation of (R)‐DCE‐CP. These results suggest that different enzymes are responsible for the formation of (S)‐DCE‐CP from (S)‐CP and (R)‐DCE‐CP from (R)‐CP. Additionally, assuming that PHE does not affect the passive renal elimination of (R)‐ and (S)‐CP, this analysis suggests that the clearance of both (R)‐ and (S)‐CP to 4‐hydroxy‐CP (the activation pathway) is increased by PHE. Chirality 11:569–574, 1999. © 1999 Wiley‐Liss, Inc.

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Pharmacokinetics of (R)- and (S)-cyclophosphamide and their dechloroethylated metabolites in cancer patients

Cited by 27 publications

References 10 publications

Determination of cyclophosphamide enantiomers in plasma by LC‐MS/MS: Application to pharmacokinetics in breast cancer and lupus nephritis patients

Determination of cyclophosphamide enantiomers in plasma by LC‐MS/MS: Application to pharmacokinetics in breast cancer and lupus nephritis patients

P-Chirogenic silylphosphine-boranes: synthesis and phospha-Michael reactions

Enantioselective induction of cyclophosphamide metabolism by phenytoin

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