Bioactivation of cyclophosphamide: the role of polymorphic CYP2C enzymes. Eur J Clin Pharmacol 2003 Jun;59(2):103-9
Date
04/10/2003Pubmed ID
12684728DOI
10.1007/s00228-003-0590-6Scopus ID
2-s2.0-0038729519 (requires institutional sign-in at Scopus site) 71 CitationsAbstract
Several-fold differences have been observed among patients in the biotransformation of cyclophosphamide. The aim of this study was to investigate the contribution of CYP2C9 and CYP2C19 and their polymorphisms to the variability of cyclophosphamide activation. 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. The kinetic data obtained in the yeast system revealed that the intrinsic clearance (V(max)/K(m)) of cyclophosphamide by CYP2C9.2 and CYP2C9.3 samples was approximately threefold lower than that by CYP2C9.1. 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). We found a statistically significant correlation ( r(s)=0.65, P=0.003) between 4-hydroxylation of cyclophosphamide and 5'-hydroxylation of R-omeprazole, a measure of CYP2C19 activity in human liver microsomes ( n=19). No correlation was found between 4-hydroxylation of cyclophosphamide and the formation rate of hydroxycelecoxib, mainly catalysed by CYP2C9 ( r(s)=0.17, P=0.55, n=32). In conclusion, based on the correlation with the formation of R-5'-hydroxyomeprazole, CYP2C19 may partly contribute to the bioactivation of cyclophosphamide in human liver microsomes, while the role of CYP2C9 appears minor.
Author List
Griskevicius L, Yasar U, Sandberg M, Hidestrand M, Eliasson E, Tybring G, Hassan M, Dahl MLMESH terms used to index this publication - Major topics in bold
Antineoplastic Agents, AlkylatingAryl Hydrocarbon Hydroxylases
Celecoxib
Cyclophosphamide
Cytochrome P-450 CYP2C19
Cytochrome P-450 CYP2C9
Genotype
Humans
Hydroxylation
In Vitro Techniques
Microsomes
Microsomes, Liver
Mixed Function Oxygenases
Omeprazole
Polymorphism, Genetic
Pyrazoles
Saccharomyces cerevisiae
Sulfonamides