The pharmacokinetics and pharmacodynamics of metoprolol after conventional and controlled-release administration in combination with hydrochlorothiazide in healthy volunteers.
We have studied a controlled-release formulation containing metoprolol 100 mg and hydrochlorothiazide 12.5 mg. We compared the pharmacokinetics of both substances and the pharmacodynamics of metoprolol with those of a conventional combination tablet. The controlled-release formulation gave less variable plasma metoprolol concentrations, Cmax 138 nmol.l-1 and Cmin 74 nmol.l-1, whereas for the conventional formulation the mean Cmax of metoprolol was 629 nmol.l-1 and the Cmin 20 nmol.l-1. Despite lower relative systemic availability (68%) for metoprolol from the controlled-release formulation and a smaller AUC, metoprolol from the controlled-release formulation produced a greater total effect, calculated as the area under the curve of the effect on exercise heart rate vs. time (303 vs. 259%.h; P < 0.05). Hydrochlorothiazide was rapidly absorbed from both formulations and the plasma concentration profiles were almost superimposable. Controlled-release metoprolol with hydrochlorothiazide combines effective beta 1-adrenoceptor blockade for 24 h without affecting the pharmacokinetics of hydrochlorothiazide.
Lundborg
P
P
Clinical Pharmacology, Clinical Research and Development, Astra Hässle AB, Mölndal, Sweden.
Abrahamsson
B
B
Wieselgren
I
I
Walter
M
M
D000328:Adult; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004338:Drug Combinations; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
D003692:Delayed-Action Preparations; D004338:Drug Combinations; D006852:Hydrochlorothiazide; D008790:Metoprolol