The pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, disopyramide, were investigated in 12 volunteers who took 300 mg doses of 3 different capsule preparations and an aqueous oral solution of the drug at 1-week intervals. Concentrations of drug unbound to plasma proteins were measured by a sensitive immunoenzyme assay after ultrafiltration of plasma samples taken serially after dosing. QT interval was measured on serial ECG recordings with correction for changes in heart rate. Unbound concentrations of disopyramide were modelled by an open one-compartment pharmacokinetic model with a zero-order absorption rate and a lag time. There was no significant difference in parameter estimates between the four preparations, except for the lag time, which was significantly shorter for the solution preparation. The saturable protein binding of disopyramide was described by a hyperbolic model including a specific binding site and additional nonspecific binding. The pharmacodynamic relationship between unbound drug concentration and QT prolongation was fit by a simple linear model. This fit was better using unbound concentration of the drug than using total concentrations.

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In this study we compared the absorption and disposition of two commonly used combination formulations of hydrochlorothiazide and triamterene (Dyazide and Maxzide) in 48 patients with essential hypertension after dosing with each formulation to steady state. Interdose AUC and urinary recovery of hydrochlorothiazide, triamterene, and the major metabolite of triamterene, hydroxytriamterene sulfate (adjusted for dose), documented marked impairment in the absorption of hydrochlorothiazide (approximately two third as bioavailable) and triamterene (about half as bioavailable) from Dyazide in comparison to Maxzide. The study also demonstrated a reduction in the clearance of triamterene, hydrochlorothiazide, and hydroxytriamterene sulfate with increasing age. Linear correlation analyses suggested that this effect was a result of the reduction in renal function that occurs with increasing age.

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