title: Effect of intestinal first-pass hydrolysis on the oral bioavailability of an ester prodrug of fexofenadine.
abstract: The contribution of intestinal first-pass hydrolysis to oral bioavailability was evaluated in rats using a model prodrug of fexofenadine (FXD), which has poor oral bioavailability. The prodrug, ethyl-FXD, has high membrane permeability but the oral bioavailability of FXD derived from ethyl-FXD was only 6.2%. Ethyl-FXD was not detected in the plasma, whereas FXD was detected, indicating complete first-pass hydrolysis. In in vitro experiments, hydrolase activity for ethyl-FXD was higher in the liver and blood than that in the intestine. However, the high blood protein binding of ethyl-FXD resulted in a high hepatic availability (F(h) = 88%). The complete bioconversion of ethyl-FXD in the in vivo oral administration is difficult to explain by first-pass hydrolysis in the liver and blood. Interestingly, in an in situ rat jejunal single-pass perfusion experiment, 84% of the ethyl-FXD taken up into enterocytes was hydrolyzed. Furthermore, only one-fifth of the FXD formed in mucosa reached the mesenteric vein because of its P-glycoprotein-mediated efflux into the intestinal lumen. These findings indicate that the intestinal bioconversion of ester prodrugs to their parent drugs is a key factor in determining their oral bioavailability.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ohura
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Soejima
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nogata
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Adachi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ninomiya
authors.forename: Teruko
authors.initials: T
authors.lastname: Imai
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001711:Biotransformation; D002626:Chemistry, Pharmaceutical; D020895:Enterocytes / Q000378:metabolism; D039563:Histamine H1 Antagonists, Non-Sedating / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006867:Hydrolases / Q000378:metabolism; D006868:Hydrolysis; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013678:Technology, Pharmaceutical / Q000379:methods; D016593:Terfenadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D039563:Histamine H1 Antagonists, Non-Sedating; D011355:Prodrugs; C548663:ethyl fexofenadine; D016593:Terfenadine; C093230:fexofenadine; D006867:Hydrolases