CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects.

Purpose: 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-∞.

Conclusion: 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.