Genetic polymorphisms of CYP2B6 affect the pharmacokinetics/pharmacodynamics of cyclophosphamide in Japanese cancer patients

Pharmacogenet Genomics. 2007 Jun;17(6):431-45. doi: 10.1097/FPC.0b013e328045c4fb.


Objective: To evaluate the effects of genetic polymorphisms of drug metabolizing enzymes on the pharmacokinetics of cyclophosphamide and its active metabolite, 4-hydroxycyclophosphamide, and on the pharmacodynamics.

Experimental design: One hundred and three Japanese patients with malignant lymphoma or breast cancer treated with cyclophosphamide (500-750 mg/m) participated in this study. The plasma concentrations of cyclophosphamide and 4-hydroxycyclophosphamide were determined by high-performance liquid chromatography, and pharmacokinetic parameters were calculated. The genotypes of CYP2B6, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, GST genes were determined by allele-specific polymerase chain reaction or polymerase chain reaction-restriction-fragment length polymorphism.

Results: A large interindividual difference (54-fold) was observed in the area under the curve ratio of 4-hydroxycyclophosphamide/cyclophosphamide calculated as the metabolic index. We first proved that leukocytopenia and neutropenia were significantly (P<0.01) related to the area under the curve of 4-hydroxycyclophosphamide. We found that the homozygotes of CYP2B6*6 (Q172H and K262R) showed significantly (P<0.05) higher clearance and shorter half-life of cyclophosphamide than heterozygotes and homozygotes of CYP2B6*1. The small sample size, however, limited the impact. On the other hand, it was clearly demonstrated that the patients possessing the single nucleotide polymorphisms of the CYP2B6 gene, g.-2320T>C, g.-750T>C (5'-flanking region), g.15582C>T (intron 3), or g.18492T>C (intron 5), had significantly lower area under the curve ratios of 4-hydroxycyclophosphamide/cyclophosphamide, indicating a decreased cyclophosphamide 4-hydroxylation. Of particular importance was the finding that leukocytopenia was significantly related to the single nucleotide polymorphisms g.-2320T>C, g.-750T>C, and g.18492T>C in CYP2B6 gene, which are highly linked. No relationship was observed between the pharmacokinetics of cyclophosphamide or 4-hydroxycyclophosphamide and genetic polymorphisms of the other enzymes.

Conclusions: We clarified that the single nucleotide polymorphisms in the promoter region or introns in the CYP2B6 affect the potency of cyclophosphamide activation to 4-hydroxycyclophosphamide. This information would be valuable for predicting adverse reactions and the clinical efficacy of cyclophosphamide.

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use
  • Aryl Hydrocarbon Hydroxylases / genetics*
  • Base Sequence
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Cyclophosphamide / adverse effects
  • Cyclophosphamide / analogs & derivatives
  • Cyclophosphamide / pharmacokinetics*
  • Cyclophosphamide / therapeutic use
  • Cytochrome P-450 CYP2B6
  • DNA, Neoplasm / genetics
  • Female
  • Gene Frequency
  • Genotype
  • Humans
  • Introns
  • Japan
  • Lymphoma / drug therapy
  • Lymphoma / genetics*
  • Lymphoma / metabolism*
  • Male
  • Middle Aged
  • Oxidoreductases, N-Demethylating / genetics*
  • Pharmacogenetics
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic


  • Antineoplastic Agents
  • DNA, Neoplasm
  • 4-hydroxycyclophosphamide
  • Cyclophosphamide
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating