Mechanism of the pharmacokinetic variability and race difference of β-blockers

We evaluated the effect of genetic polymorphisms of CYP (2D6, 2C9, 2C19, 3A5) and UDP-glucuronosyl-transferase (UGT) 2B7, and multidrug resistance 1 (MDR1) on the pharmacokinetics of carvedilol in healthy Japanese volunteers. The CL/F value of R- and S-carvedilol was significantly decreased in patients with CYP2D6^*10 allele, suggesting that CYP2D6^*10 is one of the major factors responsible for large pharmacokinetic variability of the drug. In contrast, the pharmacokinetic variability of bisoprolol was small in Japanese patients, provided that both body weight and renal function are taken into account for the prediction of CL/F of the drug. In addition, we elucidated the pharmacokinetics of bisoprolol in rats with experimental renal failure, and then evaluated the effect of renal failure on the pharmacodynamics of bisoprolol ; however, β-blocking action of the drug was not altered by renal failure. Our results may provide useful information about the use of β-blockers in management of heart failure.