Quinidine pharmacokinetics in man: Choice of a disposition model and absolute bioavailability studies

Abstract

Parameters describing disposition and absolute oral bioavailability of quinidine were determined in ten normal male volunteers using a specific assay. Various models were compared for their ability to describe the experimental data. An intravenous quinidine gluconate and an oral quinidine sulfate solution were administered (3.74 mg/kg quinidine base). In three subjects the intravenous and oral studies were repeated. One-, two-, and three-compartment models with zero and first-order input were fitted to the plasma concentrations. The selection of the best model was made by the Akaike information criterion and by eye. After intravenous administration, plasma concentration-time curves could be adequately described by a two-compartment model. Mean disposition constants (+/- SD) were obtained from individualized fits (V1: 0.398 +/- 0.336 LITER/KG, Vdarea: 2.53 +/- 0.72 liter/kg, alpha: 0.316 +/- 0.294 min -1, beta: 0.00204 +/- 0.00262 min -1, k2: 0.0305 +/- 0.0101 min -1). A clearance of 4.9 +/- 1.5 ml/min/kg was observed. After oral administration, three-compartment models were needed to describe the observed data in some cases. Absorption was in most cases best described by a zero-order rather than by a first-order process. The time to peak concentration varied from 23 to 121 min, the lag time was always less than 3 min, and the mean elimination rate constant was 0.00171 min -1. The mean oral bioavailability of quinidine was 0.70 +/- 0.17.

The effect of quinidine and its metabolites on the electrocardiogram and systolic time intervals: concentration‐effect relationships.

“…Quinidine is extensively metabolized after oral administration (up to 30% during absorption) (Guentert, Holford et al, 1979) and levels of some of the metabolites after oral dosing to steady state may equal or exceed quinidine in serum water (Drayer et al, 1978). A new metabolite of quinidine, an Noxide, was found in the plasma of our subjects , and, in some, reached 30% of simultaneous quinidine concentrations after oral dosing.…”

“…The effect-compartment 'concentrations' are equivalent to the steady state plasma concentrations causing the same effect. Plasma concentrations are modelled by standard two-compartment pharmacokinetic models (Guentert, Holford et al, 1979;Ueda & Dzindzio, 1978). The relationship between effect-compartment concentration and effect is evaluated using a simple linear pharmacodynamic model (Equations la and lb).…”

“…The bioavailability of a quinidine sulphate solution was studied in ten normal volunteers (Guentert, Holford, Coates, Upton & Riegelman, 1979 0,5,10,15,25,30,40,45,50,60,75,90,105,120,180,240,300,360,420,480,840 and 1440 min after administration of i.v. and oral doses of quinidine or placebo.…”

“…Plasma was separated within 15 min and frozen at -20°C until analyzed using a specific assay for quinidine (Guentert, Holford et al, 1979).…”

“…Plasma concentrations of quinidine were fit to a two-compartment pharmacokinetic model (Guentert, Holford et al, 1979) using an interactive (Holford, 1979a) nonlinear least squares fitting program (Knott, 1979).…”