Comparison of Assay Procedures Used to Measure Total and Unbound Concentrations of Quinidine

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Individualized quinidine dosing through the assessment of serum concentrations is warranted because of the wide variability observed in its pharmacokinetic behavior and its reported narrow therapeutic index. The free fraction of quinidine also varies widely. Thus the development of procedures that could be widely used to determine quinidine free concentrations would be highly desirable. It was the purpose of this study to evaluate several procedures available to determine total serum quinidine concentrations (rate nephelometry [ICS], homogenous enzyme immunoassay [EMIT], and high-performance liquid chromatography [HPLC]). Furthermore, in samples from 46 patients, equilibrium dialysis and ultrafiltration procedures were compared for their ability to estimate quinidine free fraction. Finally, unbound concentrations of quinidine were compared using a modified EMIT procedure and a standard HPLC method to quantitate quinidine in ultrafiltrates from patient samples. For the measurement of total quinidine concentrations, reasonable agreement was seen when EMIT and ICS systems were compared with HPLC (ICS = 1.03 · HPLC +0.96, r=0.93;EMIT= 1.08 · HPLC + 0.38, r=0.93) The mean errors, however, for these procedures were high (ICS +70 percent, range +7 to +233 percent; EMIT + 35 percent, range 0 to 110 percent). Quinidine free fractions (QFF) determined by equilibrium dialysis (E) and ultrafiltration (U) showed good agreement (QFF(U) = 1.11 · QFF(E) + 0.0; r = 0.96). Unbound quinidine concentration determined by EMIT analysis of ultrafiltrate substantially overestimated the values obtained by HPLC analysis (mean error by EMIT 104 ± 59 percent). It is concluded that HPLC is the method of choice for determining both total and unbound serum quinidine concentrations. The EMIT procedure on average produces acceptable error for the measurement of total quinidine concentrations; however, errors greater than 100 percent do occur. Thus, caution should be used when interpreting the results of the EMIT procedure. For determining unbound concentrations the EMIT produces unacceptable error and the HPLC method should be used to obtain reliable estimates of free quinidine concentrations.

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