title: 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 beta-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 (Vss) 673 l; volume corrected by real body weight (Vss.kg-1) 11.2 l.kg-1; total clearance (CL) 51.6 h-1; and terminal half-life (t1/2) 10.3 h. The Vss (898 l) and CL (71.6 l.h-1) were significantly higher in obese patients. But Vss.kg-1 (9.4 l.kg-1) and t1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15-18 l.h-1) and the t1/2 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Service de Pharmacologie, Hôpital St Antoine, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Cheymol
authors.forename: R
authors.initials: R
authors.lastname: Woestenborghs
authors.forename: E
authors.initials: E
authors.lastname: Snoeck
authors.forename: R
authors.initials: R
authors.lastname: Ianucci
authors.forename: J P
authors.initials: JP
authors.lastname: Le Moing
authors.forename: L
authors.initials: L
authors.lastname: Naditch
authors.forename: J C
authors.initials: JC
authors.lastname: Levron
authors.forename: J M
authors.initials: JM
authors.lastname: Poirier
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000328:Adult; D001578:Benzopyrans / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004983:Ethanolamines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D000068577:Nebivolol; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D008055:Lipids; D000068577:Nebivolol