Effects of Verapamil on P-R-intervals in Relation to Verapamil Plasma Levels Following Single I.V. and Oral Administration and During Chronic Treatment

A close relationship between verapamil plasma concentration and effect on P-R interval could be established both after single i.v. and oral administration and during chronic oral treatment. After i.v. administration a linear relationship between verapamil plasma concentration and delta P-R (y=x (0.74) + 1.8) with a small between subject variation in the slope of the regression (%coefficient of variation 18.7, range 0.71-1.10) was observed. The slope of the oral plasma concentration response regression (y=x (0.33)-3.0) was statistically significantly (p less than 0.05) less than the slope of the i.v. plasma level response regression. Interindividual variation in the slope was most pronounced (range 0.13 to 0.47). On average two to three times higher verapamil plasma levels were required after oral administration in order to produce the same increase in delta PR as after intravenous administration. The most plausible explanation for the different slopes of the plasma level response regression seems to be stereo-selective presystemic elimination. Since after oral administration the plasma level response curve is less steep than after i.v. administration this indicates that the more active l-isomer is preferentially metabolized during hepatic first-pass metabolism.