title: CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects.
abstract: OBJECTIVE
  The pharmacokinetics (PK) of labetalol show wide inter-subject variability, but the genetic causes for this are largely undetermined. This study was performed to examine whether common polymorphisms in UGT1A1, UGT2B7, CYP2C19 and ABCB1 affect the PK of labetalol.
  
  
  METHODS
  The PK of labetalol were determined in 37 Chinese healthy male subjects who took a single oral dose of 200 mg labetalol. Plasma concentrations of labetalol were determined by a high-performance liquid chromatographic method. Subjects were genotyped for the CYP2C19 2 and 3, UGT1A1 6, 28 and 60, UGT2B7 2 and ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms.
  
  
  RESULTS
  Subjects with the CYP2C19 2/ 2 genotype had a higher peak concentration (255.5 ± 80.1 vs. 156.0  ±  66.3 ng/mL; P < 0.05) and area under the concentration-time curve (AUC0-∞; 1,473.7 ± 493.6 vs. 502.8 ± 176.1 ng[Symbol: see text]h/mL; P < 0.001) than subjects with 60 or 28, and UGT2B7 2 did not result in a significant effect. Subjects with ABCB1 2677TA or TT or ABCB1 3435TT genotypes had higher AUC0-∞ and lower total clearance than the wild-types (P < 0.05), but this appeared to be related to the distribution of CYP2C19 genotypes. The CYP2C19 genotype appeared to be the only predictor of labetalol concentrations, accounting for approximately 60 % of the total variance in the AUC0-∞.
  
  
  CONCLUSIONS
  Our results suggest that the PK of labetalol are significantly affected by the common CYP2C19 polymorphisms in individuals of Chinese ethnicity. Future larger studies are needed to evaluate the effect of CYP2C19 and UGT1A1 polymorphisms on the PK of labetalol stereoisomers and the pharmacodynamic effects.
authors.affiliation: Department of Medicine and Therapeutics, The Chinese University of Hong Kong-Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
authors.forename: Sze Wa
authors.initials: SW
authors.lastname: Chan
authors.forename: Miao
authors.initials: M
authors.lastname: Hu
authors.forename: Sara Shun Wah
authors.initials: SS
authors.lastname: Ko
authors.forename: Catherine Wing Yan
authors.initials: CW
authors.lastname: Tam
authors.forename: Benny Siu Pong
authors.initials: BS
authors.lastname: Fok
authors.forename: Ophelia Qi Ping
authors.initials: OQ
authors.lastname: Yin
authors.forename: Moses Sing Sum
authors.initials: MS
authors.lastname: Chow
authors.forename: Brian
authors.initials: B
authors.lastname: Tomlinson
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002681:China; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D007741:Labetalol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D011110:Polymorphism, Genetic; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D007741:Labetalol