1 A combined pharmacokinetic and pharmacodynamic model has been used to analyze the relationship between electrocardiographic (ECG) and systolic time intervals (STI) and changes in plasma concentration of quinidine after oral and i.v. doses in ten normal subjects. 2 The major effects of quinidine were on cardiac repolarization. Contrary to previous descriptions, we found no important change in the U wave, but the T wave was split into two peaks. The amplitude of these two peaks (T and T') was reduced, and the QT' peak and QT intervals were prolonged. The QT peak interval and systolic intervals did not change appreciably. There were small increases in the PQ and QRS intervals. 3 The effect of quinidine on the QT interval could be explained by a linear pharmacodynamic model. The equilibration between plasma and effect site had a half‐time of 8 min. The slope of the pharmacodynamic model was 20.3 ms . mg 1(‐1) after i.v. dosing and 33.5 ms . mg 1(‐1) after oral dosing. 4 The difference in effect model slopes suggests pharmacologically active metabolites of quinidine are formed during absorption from the gut. 5 The total effect of a single oral dose of quinidine appears to be the same as the same dose given intravenously, even though only 70% of the oral dose reaches the systemic circulation as quinidine.

1 During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. 2 Ro 15-1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 1 kg-l. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.141 min1 resulted in a short elimination half-life of less than 1 h. 3 No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics. 4 Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. 5 Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20-90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.

1 The influence of a-interferon (Roferon-A®) on the pharmacokinetics and metabolism of theophylline was studied in healthy adults. Roferon-A was administered as an intramuscular injection (3 x 106 iu) once-a-day over 3 days. One week prior to and immediately after this course a single 20 min aminophylline infusion (4 mg kg-') was given.2 Blood samples for theophylline analysis were taken over 48 h. Urine was collected up to 72 h and assayed for theophylline and its major metabolites 3-methylxanthine, 1,3-dimethyluric acid and 1-methyluric acid. 3 Pharmacokinetic parameters for theophylline in plasma were calculated. From urinary excretion data the overall metabolic clearance of theophylline and clearances for formation of the metabolites were calculated. 4 After interferon administration, there was a significant increase of approximately 15% in the mean values of the terminal elimination half-life, area under the curve and mean residence time of theophylline in association with a similar decrease in plasma clearance (P < 0.05). Formation clearances of the metabolites tended to be smaller after treatment, but only the change in the overall clearance of theophylline was significantly different (P < 0.05). There was no systematic shift in the metabolic pattern of theophylline.5 Additional investigations of the influence of the duration of CL-interferon treatment are necessary before definite conclusions can be drawn about the mechanism and the clinical relevance of the described interaction.