Pharmacokinetics of Quinidine in Male Patients

Abstract

Quinidine pharmacokinetic behaviour was evaluated in 139 adult hospitalised men receiving oral quinidine therapy. A total of 391 serum quinidine concentrations were measured by enzyme immunoassay for routine clinical purposes. The NONMEM programme was used to examine the relationship between quinidine pharmacokinetics and several potential covariates. A 1-compartment open model with first-order absorption and elimination was assumed. The mean apparent volume of distribution (Vd) was about 230L. When measured, alpha 1-acid glycoprotein (AAG) levels were not included in the analysis. Oral quinidine clearance (CL) decreased with age, severe congestive heart failure and renal disease, and increased in patients with a history of alcohol abuse. The interpatient variability in CL and the intrapatient residual variability expressed as coefficients of variation (CV) were 28 and 31%, respectively. When AAG values were incorporated into the analysis, the only important covariates of CL were the AAG measurements and the presence of renal dysfunction as indicated by a calculated creatinine clearance of less than 50 ml/min (3 L/h). The interpatient variability in CL and the residual intrapatient CVs decreased to approximately 24 and 26%, respectively. Improvement of the CL model by inclusion of measured AAG strongly suggests that quinidine elimination is dependent on the free concentration of drug in plasma and supports the use of free serum quinidine concentrations when evaluating and monitoring quinidine therapy.

Mixed-Effects Models in S and S-PLUS

“…A.25 Quinidine-Quinidine Kinetics Verme, Ludden, Clementi and Harris (1992) analyze routine clinical data on patients receiving the drug quinidine as a treatment for cardiac arrythmia (atrial fibrillation of ventricular arrythmias). All patients were receiving oral quinidine doses.…”

Quinidine

“…8,9 After oral administration it is almost completely absorbed and is distributed rapidly to most tissues except brain tissue. The usual oral dose of quinidine sulfate is 200 to 400 mg Q three or four times a day, and steady-state plasma concentrations are reached within 24 hours.…”

“…12 Monitoring of plasma quinidine concentrations is potentially useful, because the pharmacokinetic characteristics vary considerably from one person to another. 8,9,[13][14][15] The elimination half-life of quinidine ranges between 3 and 19 hours, 8,11 with elimination due both to renal excretion of the intact drug (accounting for 15 to 40 percent of the total amount ingested) and to hepatic 3-hydroxylation and N -oxygenation catalyzed by cytochrome CYP3A4. 16 The products (e.g., 3-hydroxyquinidine and quinidine-N -oxide) are less electrophysiologically active than the parent compound.…”

“…The oral administration of quinidine to convert atrial fibrillation to sinus rhythm can be effective but is potentially dangerous and inconvenient, in view of *Data are from Ueda, 8 Verme et al, 9 Wooding-Scott et al, 10 and Benet et al 11 Plus-minus values are means Ϯ SD. †The rate but not the extent of absorption is reduced when quinidine is taken with food.…”

Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

“… a Taken from Scavone et al (1989 [140], 1997 [141]) and Thompson et al [142]; b taken from Rumble et al [143]; c taken from Birkett and Miners [144]; d taken from Brogard et al [145]; e taken from Larson et al [146]; f taken from Stuck et al [147]; g taken from Setchell et al [148]; h taken from Hughes, Ilett and Jellett [149] and Verme et al [150]; and i taken from Bres and Bressolle [140]. …”