Disopyramide serum and pharmacologic effect kinetics applied to the assessment of bioavailability.

Abstract

I Serum, urine and pharmacologic effect (prolongation of the QT interval) kinetics of the antiarrhythmic disopyramide have been investigated in eight volunteers after intravenous administration (2 mg/kg) and oral administration (300 mg) of the two commercially available preparations, Rythmodan (Roussel Laboratories) and Norpace (Searle Laboratories). 2 An open one compartment body model adequately described the kinetics of disopyramide in serum and urine. 3 After intravenous administration, the following average pharmacokinetic parameters were found: biological half-life, 7.8 h; total clearance, 95 ml/min; renal clearance, 54 ml/min; apparent volume of distribution, 60 litres. 4 After oral Rythmodan and Norpace, serum concentration profiles and urinary excretion data revealed significant differences in rates of absorption, times required to achieve peak serum concentrations and biological half-lives. These differences were largely due to the relatively slow absorption characteristics of Norpace. SThe absence of hysteresis in plots of QT prolongation against disopyramide serum concentration after oral administration indicated that serum and pharmacologic effect kinetics were indistinguishable within a kinetically equivalent compartment. 6 Analysis of both serum and urine data showed that while Norpace had a significantly higher degree of bioavailability (P< 0.005), the 5-15% difference between the two formulations should not normally be of any clinical significance.

Disopyramide pharmacokinetics during recovery from myocardial infarction.

“…However, it has been shown that drug distribution is extremely rapid (Hinderling & Garrett, 1976) (Bryson et al, 1978;: observation is consistent with s( (Rango et al, 1976 Karim, 1975 …”

“…This employed a Perkin Elmer F33 gas liquid chromatograph equipped with a Perkin Elmer nitrogen/phosphorus detector. Details of the extraction procedure, operating conditions, and assay precision have been published previously (Bryson et al, 1978).…”

“…A previous pharmacokinetic study in normal, young, healthy male volunteers (Bryson et al, 1978) showed that disopyramide total body clearance is of the order of 95 ml/min and that the elimination halflife ranges from 6-10 h. The parent drug is excreted unchanged by glomerular filtration and approximately 25% of a dose is metabolised to mono-Ndealkyldisopyramide. The plasma protein binding is saturable and depends on both parent drug and metabolite concentrations (Hinderling et al, 1974).…”

A chemically stable analogue, 9 beta‐methyl carbacyclin, with similar effects to epoprostenol (prostacyclin, PGI2) in man.

“…Ten cardiac cycles were measured and averaged for each determination of systolic time intervals and for each ECG. The QS2 interval, left ventricular ejection time (LVET) and the QT interval on the ECG were corrected for heart rate using regression equations derived previously (Burgess et al, 1978;Bryson et al, 1978): QS2 index = QS2 (in ms) + (1.2 x heart rate); LVET index = LVET + (1.1 x heart rate); pre-ejection period (PEP) requires no correction for heart rate; QT index = QT + (1.7 x heart rate) and corrected QT interval 93-methyl carbacyclin and epoprostenol in man…”

Quantitative analysis of the disopyramide concentration‐effect relationship.

“…A recent paper on the assessment of disopyramide bioavailability (Bryson, Whiting & Lawrence, 1978) presented pharmacodynamic data which suggested that prolongation of the QT interval after oral administration was directly proportional to the plasma disopyramide concentration. Effect and concentration were plotted against each other on linear axes and the degree of hysteresis, i.e.…”