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.

I A combined pharmacokinetic-pharmacodynamic model has been used to analyse the relationship between QT prolongation and changes in plasma concentration which occurred after disopyramide was given intravenously and orally to eight healthy subjects. 2 The pharmacokinetic models appropriate to intravenous and oral disopyramide have been extended by an 'effect compartment' which has no influence on the predetermined mass of drug in the body. 3 The model incorporates an adjustment for lag of effect behind any rapid changes in plasma concentration such as occur in the early distributive phase following intravenous administration. This permits calculation of the proportionality constant relating plasma concentration to effect. 4 Irrespective of the route of administration the mean (± s.d.) prolongation of the QT interval was 14.5 + 6.5 ms/jig ml-'. 5 There was no evidence that metabolite produced during first pass after oral administration made any significant contribution to effect. 6 This modelling technique should be applicable to the study of the concentration-effect relationship of a number of other drugs, both in health and in disease.

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Pyridostigmine kinetics were examined under conditions of clinical use as an antagonist of nondepolarizing neuromuscular blockade in anesthetized patients with and without renal function. Pyridostigmine serum levels were assayed by gas-liquid chromatography, and data were fitted to a 2-compartment kinetic model. Pyridostigmine kinetics following renal transplantation (n = 5) were not different from those in patients with normal renal function. Renal function (n = 5) elimination half-life increased from 112 -± 12 min (S ± SD) to 379 -± 162 mm, and serum clearance decreased from 9 ± 2 ml/kg/min to 2 ± 0.6 ml/kg/min in anephric patients (n = 4). We conclude that renal function accounts for 75% of pyridostigmine clearance.Impaired renal function decreases plasma clearance and prolongs duration of action of some nondepolarizing muscle relaxants, which may account for problems of prolonged neuromuscular blockade in patients with renal failure.12-13' 15' 19 We recently found that renal failure also decreased plasma clearance and prolonged elimination half-life of neostigmine, an antagonist of nondepolarizing neuromuscular blockade.4 We wondered whether this also applied to another common antagonist, pyridostigmine, which has a slower onset and longer duration of antagonist activity in anesthetized patients than neostigmine.16 Therefore pyridostigmine kinetics were examined in patients with and without renal function and after kidney transplantation. We also sought to determine

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