Assessment of quinidine gluconate for nonlinear kinetics following chronic dosing

Two different chronic dosing regimens of quinidine gluconate were administered to each of four healthy volunteers in a pilot study to evaluate quinidine for nonlinear pharmacokinetics. Analysis of plasma quinidine levels following the last dose indicates that disproportionate increases in steady-state plasma concentrations can occur in some subjects as the daily dose increases. Measurement of 2'-oxoquinidinone (2'-OXO) and 3-hydroxyquinidine (3-OH) metabolites revealed that the formation of 2'-OXO is proportional to the availability of quinidine base. Hydroxylation was a more variable process. Rate-limited hydroxylation was documented in one subject, and an apparent increase in hepatic microsomal enzyme-mediated hydroxylation was shown in a second subject who ingested large amounts of caffeine daily. By using a highly selective high-performance liquid chromatography assay technique, the total body clearance of quinidine was found to be greater than previously published data. Our results suggest that some individuals may exhibit dose-dependent elimination of quinidine and that the variability in quinidine's pharmacokinetics is related in part to its hydroxylation. Future studies must use highly specific quinidine assays and control for variables that may influence this route of metabolism.