Relationship between loperamide-induced sedative effect and digoxin pharmacokinetics in healthy Japanese subjects

Purpose. Loperamide-induced suppressive effects on central nervous system closely relate to a lack of or decline in the P-glycoprotein (P-gp) function. The aim of this study was to determine the loperamide-induced sedative effect quantitatively and to investigate possible alterations in the pharmacokinetics of digoxin, a substrate for P-gp, in Japanese subjects. Methods. Loperamide hydrochloride (2 mg) was administered orally to 26 subjects and the critical flicker-fusion frequency threshold (CFF) values were measured every 30 min separately by portable instrument. Further, digoxin (0.25 mg) was administered to 8 subjects, and the plasma concentration was determined. Results. In five subjects who complained of drowsiness, the CFF values more remarkably decreased compared with those in the other subjects. The T_max and mean residence time (MRT) values of digoxin pharmacokinetics in four subjects with drowsiness were significantly lower and C_max was higher than those in four subjects with marginal effect. Moreover, there were good correlations between the CFF value-time profile and the C_max, T_max, and MRT of digoxin. Conclusions. The determination of the CFF value after oral administration of loperamide will be useful for evaluating varied P-gp function and for anticipating individual variations in the disposition of P-gp substrates in humans.