title: Effects of CYP3A5 and CYP2D6 genetic polymorphism on the pharmacokinetics of diltiazem and its metabolites in Chinese subjects.
abstract: OBJECTIVE
  To assess the possibility of using CYP2D6 10 +/- CYP3A5*3 as biomarkers to predict the pharmacokinetics of diltiazem and its two metabolites among healthy Chinese subjects. METHODS 41 healthy Chinese were genotyped for CYP3A5 3 and CYP2D6 10, and then received a single oral dose of diltiazem hydrochloride capsules (300 mg). Multiple blood samples were collected over 48 h, and the plasma concentrations of diltiazem, N-desmethyl diltiazem and desacetyl diltiazem were determined by HPLC-MS/MS. The relationships between the genotypes and pharmacokinetics were investigated.
  
  
  RESULTS
  The pharmacokinetics of diltiazem, N-desmethyl diltiazem were not significantly affected by both CYP3A5 3 and CYP2D6*10 alleles. However, the systemic exposure of the pharmacologyically active metabolites, desacetyl diltiazem, was 2-fold higher in CYP2D6 10/10 genotype carriers than in 1/10 or 1/1 ones (AUC(o-inf) of CYP2D6 1/1, 1/10 and 10/10 are 398.2 +/- 162.9, 371,0 69.2 and 726.2 +/- 468.1 respectively, p <0.05).
  
  
  CONCLUSIONS
  Two of the most frequent alleles, CYP3A5 3 and CYP2D6 10, among Chinese do not have major impacts on the disposition of diltiazem and N-desmethyl diltiazem. However, the desacetyl diltiazem showed 2-fold accumulation in individuals with CYP2D6 10/10 genotype. Despite this, the effect of genotype of CYP2D6 on clinical outcome of diltiazem treatment is expected to be limited.
authors.affiliation: Frontage Laboratories, Inc., Zhengzhou, Henan Province, China.
authors.forename: T
authors.initials: T
authors.lastname: Zheng
authors.forename: C H
authors.initials: CH
authors.lastname: Su
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: X J
authors.initials: XJ
authors.lastname: Zhang
authors.forename: T Y
authors.initials: TY
authors.lastname: Zhang
authors.forename: L R
authors.initials: LR
authors.lastname: Zhang
authors.forename: Q C
authors.initials: QC
authors.lastname: Kan
authors.forename: S J
authors.initials: SJ
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000483:Alleles; D019540:Area Under Curve; D044466:Asian People / Q000235:genetics; D001711:Biotransformation; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics*; D002681:China / Q000453:epidemiology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004110:Diltiazem / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006207:Half-Life; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D002121:Calcium Channel Blockers; D004247:DNA; C510164:CYP3A5 protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D004110:Diltiazem