A PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTION STUDY BETWEEN NEBIVOLOL AND THE H-2-RECEPTOR ANTAGONISTS CIMETIDINE AND RANITIDINE

Aims The study was designed to investigate the effects of the H-2-rece ptor antagonists, cimetidine and ranitidine on the pharmacokinetics an d 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) fo r 24 h before and 48 h after a single oral dose of nebivolol (5 mg). N ebivolol and its individual (+) and (-) enantiomers were determined tb y h.p.l.c. Results Ranitidine had no significant effect on nebivolol p harmacokinetics. Cimetidine, however, resulted in a 21-23% increase in C-max of unchanged nebivolol and of each enantiomer plus its hydroxyl ated 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 (1.7 5, 8.76) ng ml(-1) h with cimetidine], (+)-nebivolol plus its hydroxyl ated 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 su ggest any consistent effects of ranitidine or cimetidine upon the phar macodynamic effects of nebivolol. Conclusions There was no interaction between ranitidine and nebivolol. Although cimetidine inhibited nebiv olol metabolism, it did not have a significant influence on the pharma codynamics of the drug.