Biol. Pharm. Bull. 29(3) 522—526 (2006)

ization with a pKa value of pH 8.8, is classified as a type IA antiarrhythmic drug, and has been used for the management of ventricular arrhythmias. The drug is absorbed rapidly and almost entirely after oral administration, and is detected in the plasma within 15 min. Quinidine binds to both albumin and a1-acid glycoprotein, and the proportion that binds to plasma protein is 70 to 95%. However, its apparent volume of distribution is quite large (2.0 to 3.5 liters/kg), because the drug is highly lipophilic. It is metabolized via 3hydroxylation and N-oxygenation by cytochrome P450 3A4, and these metabolites are less electrophysiologically active than the parent drug. The hepatic extraction ratio of quinidine is about 30%, and the bioavailability after oral administration is about 70%. In addition, quinidine is partly excreted in the urine (15 to 40% of dose), suggesting that reabsorption at the distal tubules in the nephron is not complete. The mechanism of intestinal absorption of lipophilic organic cations has been explained as passive diffusion of unionized compounds according to the pH-partition theory. On the other hand, Mizuuchi et al. investigated the mechanisms responsible for the transcellular transport of diphenhydramine in Caco-2 cells. This cell line forms confluent monolayers of well differentiated enterocyte-like cells with functional properties of transporting epithelia, and is widely used as a model to study the absorption of drugs and other xenobiotics. The uptake of diphenhydramine at the apical membrane in Caco-2 cells was pHand temperature-dependent, but was not inhibited by tetraethylammonium, biological amines, or neurotransmitters. On the other hand, the uptake was inhibited by chlorpheniramine, procainamide, and imipramine, and was trans-stimulated by the preloading of chlorpheniramine, dimethylaminochloride, and triethylamine. From these results, Mizuuchi et al. concluded that the uptake of diphenhydramine at the apical membrane in Caco-2 cells is mediated by a specific transport system, and that this system recognizes the N-dimethyl or N-diethyl moieties of compounds. However, at present, it is unclear whether the transport system for diphenhydramine is involved in the intestinal absorption of other tertiary amine compounds, such as quinidine. During drug absorption in the intestine, therapeutic compounds or nutrients first enter intestinal epithelial cells from their apical side, then pass through the epithelia to the basolateral side, and finally appear in the blood stream. Therefore, to investigate intestinal drug absorption, it is important to separately assess these sequential processes. However, in many cases, drug transport on the apical and basolateral sides of the monolayer in Caco-2 cells was not separately examined, and the influx and efflux clearance rates were not evaluated. For the characterization of transcellular drug transport, a pharmacokinetic approach is useful. Transcellular drug transport in Caco-2 cell monolayers can be analyzed in detail in a model-dependent manner, where their drug concentration–time profiles on both sides of the monolayer can be assessed by curve fitting calculations and the influx and efflux clearance of the monolayer separately evaluated. In addition, when transcellular drug transport is examined under the condition where the unlabeled drug concentration in the monolayer is equilibrated with that of the incubation medium in the apical and basolateral chambers, the transport data for a small amount of radio-labeled drug can be analyzed using a linear pharmacokinetic model. In the present study, to characterize the mechanism responsible for the intestinal absorption of a lipophilic organic cation, we performed a pharmacokinetic analysis of the transcellular transport of quinidine across Caco-2 cell monolayers. This analysis indicated that the influx clearance of quinidine at the apical membrane was much greater than any other clearance values of cell membranes. Therefore, we also investigated the uptake mechanism of quinidine at the apical membrane of Caco-2 cells grown on plastic dishes. 522 Vol. 29, No. 3 Biol. Pharm. Bull. 29(3) 522—526 (2006)