Association of cyclophosphamide pharmacokinetics to polymorphic cytochrome P450 2C19.
Pharmacogenomics J
; 5(6): 365-73, 2005.
Article
en En
| MEDLINE
| ID: mdl-16116487
ABSTRACT
Cyclophosphamide (CP), a widely used cytostatic, is metabolized by polymorphic drug metabolizing enzymes particularly cytochrome P450 (CYP) enzymes. Its side effects and clinical efficacy exhibit a broad interindividual variability, which might be due to differences in pharmacokinetics. CP-kinetics were determined in 60 patients using a global and a population pharmacokinetic model considering functionally relevant polymorphisms of CYP2B6, CYP2C9, CYP2C19, CYP3A5, and GSTA1. Moreover, metabolic ratios were calculated for selected CP metabolites, analyzed by (31)P-NMR-spectroscopy. Analysis of variance revealed that the CYP2C19*2 genotype influenced significantly pharmacokinetics of CP at doses =1000 mg/m(2), whereas there was no evidence of an association of other genotypes to CP elimination or clearance. Mean (+/-SD) CP elimination constants k(e) (h(-1)) were 0.109+/-0.025 in 44 CYP2C19*1/*1 subjects, 0.088+/-0.018 in 13 CYP2C19*1/*2, and 0.076+/-0.014 in three inactive CYP2C19*2/*2 carriers (P=0.009). At CP doses higher than 1000 mg/m(2), a significantly increase of elimination was observed (P=0.001), possibly due to CYP induction. Further studies should link these findings with the clinical outcome.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Hidrocarburo de Aril Hidroxilasas
/
Ciclofosfamida
/
Oxigenasas de Función Mixta
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Adult
/
Aged
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Pharmacogenomics J
Asunto de la revista:
BIOLOGIA MOLECULAR
/
FARMACOLOGIA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Alemania