Pharmacogenetics of cyclophosphamide in patients with hematological malignancies.
OBJECTIVE
A high degree of interindividual variation in cyclophosphamide (CPA) pharmacokinetics was reported in certain cancer patient groups. To better understand the mechanisms underlying the variation in CPA metabolism, we have investigated the pharmacokinetics of CPA and its active metabolite 4-hydroxycyclophosphamide (4-OH-CPA) in patients with hematological tumors. The pharmacokinetics of CPA and its active metabolite were related to the genotype of CYP2B6, CYP2C9 and CYP2C19. The influence of liver function on CPA metabolism was also evaluated.


METHODS
Twenty-nine patients with hematological malignancies (MM, ALL or NHL) treated with a conventional CPA dose (1g/m(2)) were recruited to this study. Blood samples were collected before, during and after CPA treatment. HPLC was used to measure plasma concentrations of CPA and 4-OH-CPA. Patients were genotyped for the CYP2B6 G516T, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 alleles. Serum bilirubin levels were measured before the treatment. Data was analyzed individually and by population pharmacokinetic methods, using non-linear mixed effect modeling.


RESULTS
The interindividual variability in exposure to CPA, 4-OHCPA and 4-OH-CPA/CPA was 5.8-, 3.3- and 10.3-fold, respectively. A positive correlation between half-lives of CPA and 4-OH-CPA was found while a significant negative correlation between AUCs of CPA and 4-OH-CPA was detected. In the population analysis, the CYP2B6 G516T variant allele contribution to CPA clearance was about twice as the contribution from the wild type gene while the genotype of CYP2C9 and CYP2C19 did not influence clearance. A negative correlation was observed between bilirubin level and CPA bioactivation.


CONCLUSIONS
This study demonstrates for the first time that the presence of the CYP2B6 G516T mutation increases the rate of 4-OH-CPA formation in patients with hematological malignancies. The liver function prior therapy as assessed by s-bilirubin influences CPA metabolism.
Xie
Hanjing
H
Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, SE 141-86 Stockholm, Sweden.
Griskevicius
Laimonas
L
Ståhle
Lars
L
Hassan
Zuzana
Z
Yasar
Umit
U
Rane
Anders
A
Broberg
Ulrika
U
Kimby
Eva
E
Hassan
Moustapha
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D001663:Bilirubin / Q000097:blood; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005838:Genotype; D019337:Hematologic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics
D018906:Antineoplastic Agents, Alkylating; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; D001663:Bilirubin