A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine.
OBJECTIVE
The study was designed to investigate the effects of the H2-receptor antagonists, cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of nebivolol in healthy volunteers.


METHODS
Twelve healthy volunteers took part in a randomized placebo-controlled cross-over study. Each subject received on three separate occasions placebo, cimetidine (400 mg twice daily) or ranitidine (150 mg twice daily) for 24 h before and 48 h after a single oral dose of nebivolol (5 mg). Nebivolol and its individual (+) and (-) enantiomers were determined tby h.p.l.c.


RESULTS
Ranitidine had no significant effect on nebivolol pharmacokinetics. Cimetidine, however, resulted in a 21-23% increase in Cmax of unchanged nebivolol and of each enantiomer plus its hydroxylated metabolites. Cimetidine significantly (p < 0.05) increased the AUC [mean +/- s.d. (95% C.I. of differences in mean)] for unchanged (+/-)-nebivolol [7.76 +/- 3.07 ng ml-1 h with placebo; 11.50 +/- 5.40 (1.75, 8.76) ng ml-1 h with cimetidine], (+)-nebivolol plus its hydroxylated metabolites [73.0 +/- 18.0 ng ml-1 h with placebo; 91.5 +/- 25.7 (1.0, 23.1) ng ml-1 h with cimetidine] and (-)-nebivolol plus its hydroxylated metabolites [101 +/- 32 ng ml-1 h with placebo; 123 +/- 38 (3.3, 27.0) ng ml-1 h with cimetidine]. Statistical analysis of the resting blood pressure and heart rate and exercise data did not suggest any consistent effects of ranitidine or cimetidine upon the pharmacodynamic effects of nebivolol.


CONCLUSIONS
There was no interaction between ranitidine and nebivolol. Although cimetidine inhibited nebivolol metabolism, it did not have a significant influence on the pharmacodynamics of the drug.
Kamali
F
F
Wolfson Unit of Clinical Pharmacology, University of Newcastle, Newcastle, upon Tyne.
Howes
A
A
Thomas
S H
SH
Ford
G A
GA
Snoeck
E
E
D000328:Adult; D019540:Area Under Curve; D001578:Benzopyrans / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002927:Cimetidine / Q000494:pharmacology*; D004347:Drug Interactions; D004983:Ethanolamines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D015444:Exercise; D006339:Heart Rate / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D000068577:Nebivolol; D010919:Placebos; D011899:Ranitidine / Q000494:pharmacology*; D016037:Single-Blind Method
D001578:Benzopyrans; D004983:Ethanolamines; D006635:Histamine H2 Antagonists; D010919:Placebos; D000068577:Nebivolol; D002927:Cimetidine; D011899:Ranitidine