title: Effects of citronellal, a monoterpenoid in Zanthoxyli Fructus, on the intestinal absorption of digoxin in vitro and in vivo.
abstract: 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 [(3)H]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 [(3)H]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.
authors.affiliation: Department of Hospital Pharmacy, Toyama Medical and Pharmaceutical University, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yoshida
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Takagi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kitazawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Kawakami
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000080462:Acyclic Monoterpenes; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D039821:Monoterpenes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D032106:Zanthoxylum / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000080462:Acyclic Monoterpenes; D000447:Aldehydes; D039821:Monoterpenes; D004077:Digoxin; C108217:citronellal