Pharmacogenetic associations of CYP2C19 genotype with in vivo metabolisms and pharmacological effects of thalidomide.
Thalidomide requires cytochrome P450 (CYP)-catalyzed biotransformation for its antiangiogenic property, and CYP2C19 is responsible for 5-hydroxylation and 5'-hydroxylation of thalidomide in human. This study explored a hypothesis that patients with poor metabolizing phenotype of CYP2C19 receive little benefit from thalidomide treatment and that the poor metabolizer genotype is associated with lower ability to form the metabolites. A case-control study was conducted with 63 patients with prostate cancer who had been enrolled in a randomized phase II trial of thalidomide monotherapy (200 to 1,200 mg/day). CYP2C19 polymorphism (CYP2C19(*)2, CYP2C19(*)3, CYP2C19(*)4) was compared with clinical events (prostate-specific antigen (PSA) decline) and formations of the hydroxylated metabolites. Two patients were homozygous for the variant CYP2C19(*)2 allele (poor metabolizing phenotype). Both of these were included in the 25 patients whose PSA failed to demonstrate a decline. While 32% and 48% of the patients had quantifiable levels of 5-hydroxythalidomide and cis-5'-hydroxythalidomide, respectively, these metabolite were below quantification in both poor metabolizing patients. None had CYP2C19(*)3 or CYP2C19(*)4 alleles. Although this study had no power to detect the statistical significance of the CYP2C19 genotype, the findings were consistent with our hypothesis. The role of CYP2C19 polymorphism in thalidomide treatments remains to be elucidated.
Ando
Yuichi
Y
Molecular Pharmacology Section, Cancer Therapeutic Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Price
Douglas K
DK
Dahut
William L
WL
Cox
Michael C
MC
Reed
Eddie
E
Figg
William D
WD
D000483:Alleles; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D065731:Cytochrome P-450 CYP2C19; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D013237:Stereoisomerism; D013792:Thalidomide / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D017430:Prostate-Specific Antigen