P-glycoprotein mediated efflux in Caco-2 cell monolayers: the influence of herbals on digoxin transport.
BACKGROUND
Several herbal medicines are concomitantly used with conventional medicines with a resultant increase in the recognition of herb-drug interactions. The phytomedicines Vernonia amygdalina Delile (VA), family Asteraceae; Azadiractha indica A. Juss (NL), family Meliaceae; Morinda lucida Benth (MLB), family Rubiaceae; Cymbopogon citratus Stapf (LG), family Poaceae; Curcuma longa L. (CUR), family Zingiberaceae; Carica papaya L. (CP), family Caricaceae and Tapinanthus sessilifolius Blume (ML), family Loranthaceae are used in African traditional medicine for the treatment of malaria. They are also used in several regions world over in managing other ailments like cancer and diabetes. This study investigated their interaction with digoxin (DIG) with a view to predict the potential of P-glycoprotein (p-gp) mediated drug-herb interactions occurring with p-gp substrate drugs.


METHODS
To assess p-gp mediated transport and inhibition, bidirectional transport studies were carried out on Caco-2 cell monolayers using digoxin (DIG) as a model p-gp substrate. Cell functionality was demonstrated using the determinations of transepithelial electric resistance (TEER), cell cytotoxicity testing utilizing the MTT assay as well as the inclusion of inhibition controls.


RESULTS
Under the conditions of this study, extracts of ML, VA and CP showed significant inhibition to (3)H-Digoxin basolateral-to-apical (B-A) transport at 0.02-20mg/mL; the concentrations examined. Their apical-to-basolateral (A-B) transport was further investigated. Increases in the mean A-B transport and significant decreases in the B-A transport and efflux ratio values were observed. The apparent permeability coefficient and efflux ratio were computed providing an estimate of drug absorption.


CONCLUSIONS
The findings show that extracts of ML, VA and CP significantly inhibit p-gp in vitro and interactions with conventional p-gp substrate drugs are likely to occur on co-administration which may result in altered therapeutic outcomes.
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chiba 260-8675, Japan.
Enoche F
EF
Oga
Shuichi
S
Sekine
Yoshihisa
Y
Shitara
Toshiharu
T
Horie
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D001692:Biological Transport; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D004077:Digoxin / Q000378:metabolism*; D041743:Herb-Drug Interactions; D006801:Humans; D019684:Magnoliopsida; D016488:Medicine, African Traditional; D024301:Plant Bark; D010936:Plant Extracts / Q000494:pharmacology*; D018515:Plant Leaves
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D010936:Plant Extracts; D004077:Digoxin