INTERACTION OF PRISTINAMYCIN I-A WITH P-GLYCOPROTEIN IN HUMAN INTESTINAL EPITHELIAL-CELLS

Pristinamycin I-A is a cyclo-peptidic macrolactone antibiotic belonging to the streptogramin family. In the present work, the interaction of pristinamycin I-A with the multidrug transporter P-glycoprotein was investigated in the differentiated human intestinal epithelial cell line Caco-2 Pristinamycin I-A specifically inhibited the efflux of the P-glycoprotein substrate [H-3]vinblastine, thus increasing the cellular accumulation of the drug. Pristinamycin I-A also reduced by 70% the basolateral to apical secretion of [H-3]vinblastine across Caco-2 cell monolayers. The cellular accumulation of [C-14]pristinamycin I-A was very low and was increased by P-glycoprotein inhibitors (verapamil, chlorpromazine and reserpine). The basolateral to apical transport of [C-14]pristinamycin I-A was 100-fold higher than apical to basolateral passage. This polarized transport was inhibited by verapamil and by ATP depletion. The results suggest that pristinamycin I-A is a substrate for the P-glycoprotein, a finding which may have important consequences for the pharmacokinetics of this drug.