Determination of cyclophosphamide enantiomers in plasma by LC-MS/MS: Application to pharmacokinetics in breast cancer and lupus nephritis patients.
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.
Faculdade de Ciências Farmacêuticas de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Carolina
C
De Miranda Silva
Bruno Jose
BJ
Dumêt Fernandes
Maria Paula
MP
Marques Pereira
Lucienir Maria
LM
da Silva
Eduardo Antônio
EA
Donadi
Angelo
A
do Carmo Silva Matthes
Jurandyr
J
Moreira de Andrade
Vera Lucia
VL
Lanchote
D001774:Blood Chemical Analysis / Q000379:methods*; D001943:Breast Neoplasms / Q000097:blood* / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007700:Kinetics; D008181:Lupus Nephritis / Q000097:blood* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013379:Substrate Specificity; D053719:Tandem Mass Spectrometry; D055815:Young Adult
D003520:Cyclophosphamide