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 Tmax and mean residence time (MRT) values of digoxin pharmacokinetics in four subjects with drowsiness were significantly lower and Cmax was higher than those in four subjects with marginal effect. Moreover, there were good correlations between the CFF value-time profile and the Cmax, Tmax, 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.