Relationship between loperamide-induced sedative effect and digoxin pharmacokinetics in healthy Japanese subjects.
OBJECTIVE
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.
Kobayashi
Michiya
M
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan.
Saitoh
Hiroshi
H
Yamaguchi
Michiko
M
Saito
Takeshi
T
Fujita
Hiroyoshi
H
Suno
Manabu
M
Matsubara
Kazuo
K
Aungst
Bruce J
BJ
D000328:Adult; D044466:Asian People; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005425:Flicker Fusion / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008139:Loperamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D012894:Sleep Stages / Q000187:drug effects* / Q000502:physiology
D006993:Hypnotics and Sedatives; D008139:Loperamide; D004077:Digoxin