Myocardial uptake of encainide and its two major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, in the dog.
Encainide is a new antiarrhythmic agent which is currently undergoing clinical evaluation. Two metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE), have been identified. We have investigated the myocardial accumulation of these three compounds in an anesthetized open-chested dog model. We also considered the degree of plasma protein binding and the oil/water partitioning characteristics of these three compounds to see if they explained differences in myocardial accumulation. Each compound was administered by intravenous infusion to a group of five dogs. Blood and myocardial biopsy samplings were carried out under steady-state conditions. The myocardial/plasma concentration ratios for encainide, ODE, and MODE were 8.4, 5.4, and 4.8, respectively. The ratios were compared with a completely randomized analysis of variance followed by multiple comparisons. The myocardial/plasma concentration ratio for encainide was significantly greater (p less than .05) than the ratios of the metabolites; however, the difference between ODE and MODE was not significant. Myocardial uptake of encainide, ODE, and MODE was quite rapid, and the myocardial concentration-time course of each compound followed its time course in plasma closely. Encainide and its two metabolites are only moderately bound to plasma proteins. The mean (+/- SD) percent bound for encainide, ODE, and MODE are 49 +/- 10, 55 +/- 19, 44 +/- 18, respectively. The whole blood/plasma concentration ratios are 1.04 +/- 0.16, 1.08 +/- 0.23, and 1.06 +/- 0.08 for encainide, ODE, and MODE, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
D000813:Anilides / Q000378:metabolism*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004562:Electrocardiography; D016700:Encainide / Q000031:analogs & derivatives; D005260:Female; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011485:Protein Binding; D013997:Time Factors
D000813:Anilides; D000889:Anti-Arrhythmia Agents; D001798:Blood Proteins; C033635:O-demethylencainide; C033636:3-methoxy-O-demethylencainide; D016700:Encainide