title: Influence of cytochrome P450 2C19 gene variations on pharmacokinetic parameters of thalidomide in Japanese patients.
abstract: OBJECTIVE
  Cytochrome P450 (CYP)2C19 polymorphisms may partly explain the variability of thalidomide concentration and adverse drug effects by altering its metabolism. To compare the genetic and clinical factors responsible for the adverse effects and efficacy of thalidomide treatment, we investigated CYP2C19 genetic polymorphisms in Japanese subjects.
  
  
  METHODS
  Variations in the CYP2C19 gene in 6 patients treated with thalidomide were analyzed. The dosage of thalidomide, concentrations of (R)- and (S)-thalidomide in whole blood, and clinical laboratory test results were used as pharmacokinetic and pharmacodynamic indices. Using genomic DNA, CYP2C19*2 and *3 allele frequencies were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays.
  
  
  RESULTS
  The frequencies of CYP2C19 PM and hetero EM (hetEM) genotypes in Japanese patients taking thalidomide were 2 (33.3%) and 4 (66.7%), respectively. The areas under the curve (AUC) of (R)-thalidomide were 3.42 and 5.33 μg·h/L, and those of (S)-thalidomide were 1.64 and 2.46 μg·h/L for hetEM and PM, respectively.
  
  
  CONCLUSIONS
  This study provided new insights regarding the contribution of CYP2C19 gene variations to adverse responses to thalidomide. Genotyping of CYP2C19*2 and *3 can be considerably simplified by using KOD FX as a polymerase for prediction of adverse effects to thalidomide by the PCR-RFLP method. CYP2C19 PM patients tend to have high serum thalidomide concentrations.
authors.affiliation: Department of Pharmacy, Shinshu University Hospital, Matsumoto, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Matsuzawa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Nakamura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Matsuda
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Ishida
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohmori
mesh_terms: D000368:Aged; D000686:Amyloidosis / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism; D011110:Polymorphism, Genetic; D013792:Thalidomide / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D013792:Thalidomide; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19