Myocardial effect compartment modeling of metoprolol and sotalol: importance of myocardial subsite drug concentration.
We have recently reported the time course of acute myocardial drug uptake and simultaneous pharmacodynamic effects for metoprolol (4 mg; n = 12) and sotalol (20 mg; n = 10) in patients with ischemic heart disease. The acute pharmacodynamic effects of the two drugs included reductions in both spontaneous heart rate and the contractile index peak positive rate of left ventricular pressure rise and prolongation of the electrocardiographic PR interval, all of which exhibited an equilibration delay compared with myocardial drug content. The objective of the current study was to analyze the relationship between myocardial drug content and effect for both metoprolol and sotalol using an effect compartment model, to examine the potential for the two drugs to share a common subsite of action in the myocardium. The time course of myocardial drug content was best described by a one-compartment model for metoprolol and a two-compartment model for sotalol. A linear pharmacodynamic model, relating the amount of drug at the effect-site (Ae) with each of the three effects, was used in the effect compartment modeling. The slope of each of these effects as a function of Ae was considerably flatter for sotalol than for metoprolol, reflecting the relative beta-adrenoceptor antagonistic potencies of the two drugs. The exit rate constant from the effect compartment (K(eo)) did not differ significantly from each other or from the exit rate constant from the "peripheral" compartment (K21) for sotalol. The results suggest that the effect compartment within the myocardium for both drugs may correspond to a "peripheral" compartment, even though a "peripheral" pharmacokinetic compartment for myocardial metoprolol content was not apparent. Thus, the effect compartment for many cardioactive drugs may correspond to a pharmacokinetically "peripheral" compartment, irrespective of localization of effect to a small (e.g. sinoatrial node) or large (e.g. ventricular myocardium) region of the heart.
Ritchie
R H
RH
Department of Cardiology, Queen Elizabeth Hospital, University of Adelaide, Woodville, SA.
Morgan
D J
DJ
Horowitz
J D
JD
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D003864:Depression, Chemical; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007275:Injections, Intravenous; D016014:Linear Models; D008790:Metoprolol / Q000493:pharmacokinetics* / Q000494:pharmacology; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D012044:Regression Analysis; D013015:Sotalol / Q000493:pharmacokinetics* / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D013015:Sotalol; D008790:Metoprolol