Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects

Abstract

Objective: The pharmacokinetics of a single i.v. dose of the new racemic β-adrenoceptor-blocker nebivolol [0.073 mg base · kg-1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). Methods: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4-5 h. The plasma concentrations of the separate d- and l-enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. Results: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (V(ss)) 673 l; volume corrected by real body weight (V(ss) · kg-1) 11.2 l · kg-1 total clearance (CL) 51.6 h-1; and terminal half-life (t( 1/4 )) 10.3 h. The V(ss) (898 l) and CL (71.6 l · h-1) were significantly higher in obese patients. But V(ss) · kg-1 (9.4 l · kg-1) and t( 1/4 ) (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15-18 l · h-1) and the t( 1/4 ) prolonged (32-34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. Conclusion: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant.