title: Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2.
abstract: It has been reported that conjugating acyclovir, a potent antiviral with low oral bioavailability, to L-valine increases its urinary excretion in rats. However, it was also reported that this increase is not found for the D-valine ester, suggesting that a carrier-mediated mechanism is involved in its intestinal absorption. Therefore, mechanisms involved in the transepithelial transport of L-valine-acyclovir were investigated using the intestinal cell line, Caco-2, as a model system for the intestinal epithelium. Only the mucosal-to-serosal transport of acyclovir was increased by conjugation with L-valine (approximately 7-fold), suggesting the involvement of a carrier-mediated mechanism. This conclusion was supported by the finding that this increase was saturable. The mucosal-to-serosal transport of L-valine-acyclovir could be inhibited by L-glycylsarcosine, but not by L-valine, suggesting the involvement of the dipeptide carrier. Also it was found that L-valine-acyclovir inhibits the uptake of cephalexin, a substrate for the oligopeptide transporter. Stability of the esters in either the mucosal or serosal bathing solution is more than 90% after completion of the transport study. However, after transport, the receiver solution contained approximately 90% of acyclovir. Based on these findings it was concluded that absorption of the L-valine ester of acyclovir occurs as a result of uptake by the oligopeptide transporter at the apical cell membrane followed by intracellular hydrolysis of the ester and efflux of acyclovir.
authors.affiliation: Department of Drug Delivery, Pharmaceutical Technologies, Smithkline Beecham Pharmaceuticals, Collegeville, Pennsylvania, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: de Vrueh
authors.forename: P L
authors.initials: PL
authors.lastname: Smith
authors.forename: C P
authors.initials: CP
authors.lastname: Lee
mesh_terms: D000212:Acyclovir / Q000737:chemistry / Q000493:pharmacokinetics*; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000502:physiology*; D002506:Cephalexin / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism*; D014633:Valine / Q000493:pharmacokinetics*
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D014633:Valine; D002506:Cephalexin; D000212:Acyclovir