Effects of citronellal, a monoterpenoid in Zanthoxyli Fructus, on the intestinal absorption of digoxin in vitro and in vivo

Complementary and alternative medicines can be applied concomitantly with conventional medicines; however, little drug information is available on these interactions. Previously, we reported on the inhibitory effects of an extract and monoterpenoids (e.g., (R)-(+)-citronellal) contained in citrus herbs on P-glycoprotein (P-gp) using P-gp-overexpressed LLC-PK1 cells. The objective of the present study was to investigate the effects of (R)-(+)-citronellal on P-gp-mediated transport in the intestinal absorption process in vitro and in vivo. Transcellular transport of [3H]digoxin across Caco-2 cell monolayers was measured in the presence or absence of (R)-(+)-citronellal. (R)-(+)-citronellal reduced the basolateral-to-apical transport and efflux ratio for [3H]digoxin significantly. Serum concentration-time profiles and pharmacokinetic parameters of digoxin after intravenous and oral administration were analyzed in rats pretreated with oral (R)-(+)-citronellal. The bioavailability of digoxin after oral administration decreased significantly to 75.8% of that after intravenous administration at the same dose. (R)-(+)-citronellal increased the bioavailability of oral digoxin to 99.9% but had no effects on total body clearance, volume of distribution, or elimination rate. These findings suggest that (R)-(+)-citronellal can increase the bioavailability of oral digoxin based on the blockade of P-gp-mediated efflux of digoxin from intestinal epithelia to the lumen in the absorption process. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association.