Grapefruit juice enhances intestinal absorption of the P-glycoprotein substrate talinolol

Grapefruit juice (GFJ) is known to affect the pharmacokinetics of various d rugs, presumably mainly via inhibition of oxidative metabolism. In order to evaluate the effect of GFJ on P-glycoprotein-related transport processes, measurements of transport characteristics through Caco-2 monolayers and in vivo drug absorption studies were performed with the transported, yet not m etabolized model compound talinolol. Apical-to-basolateral talinolol transp ort in the Caco-2 model at 1 mM racemate concentration was increased almost 3-fold when GFJ was present (S-talinoloI P-eff: 0.16x10(-6) vs. 0.61x10(-6 ) cm/s without vs. with GFJ; R-talinolol P-eff: 0.19x10(-6) vs. 0.71x10(-6) cm/s without vs. with GFJ). In vivo in rats, doubled maximum plasma concen trations, enhanced AUC values (C-max of S-talinolol: control, 77.5 ng/ml vs . GFJ, 163.6 ng/ml; C-max of R-talinolol: control, 79.5 ng/ml vs. GFJ, 163. 0 ng/ml; AUC of S-talinolol: control, 19.3 mug ml(-1) min vs. GFJ, 29.9 mug ml(-1) min; AUC of R-talinolol: control, 22.2 mug ml(-1) min vs. GFJ, 30.1 mug ml(-1) min), and decreased apparent oral clearances were found for bot h talinolol enantiomers when GFJ was administered together with a racemic 1 0 mg/kg b.w. p.o. dose. Furthermore, GFJ tended to accelerate the rate of t alinolol input, but did not significantly affect terminal talinolol half-li ves. It is concluded that inhibition of intestinal secretion may contribute to bioavailability enhancement upon GFJ intake. (C) 2001 Elsevier Science B.V. All rights reserved.