title: Pharmacokinetics of erythromycin in rabbit corneas after single-dose infusion: role of P-glycoprotein as a barrier to in vivo ocular drug absorption.
abstract: Efflux pump like P-glycoprotein (P-gp) is known to be a major barrier to drug delivery. Functional P-glycoprotein has been recently identified in cornea and corneal cell lines. Thus, it is probable that P-glycoprotein may restrict in vivo ocular drug absorption, resulting in low ocular bioavailability. Experiments were designed using New Zealand albino (New Zealand White) rabbits to assess inhibitors of P-gp efflux to increase drug absorption. Anesthetized rabbits were given constant topical infusions of [(14)C]erythromycin in the presence and absence of inhibitors. Testosterone, verapamil, quinidine, and cyclosporine A were selected as P-gp inhibitors. Transport experiments were conducted in Madin-Darby canine kidney cells transfected with the human mdr1 gene (MDCK-MDR1). Erythromycin exhibited significant efflux out of MDCK-MDR1 cells, suggesting that erythromycin is a good substrate for P-gp. Ocular pharmacokinetic studies were conducted using a topical single-dose infusion method. Maximum inhibition of P-gp mediated efflux was observed with 500 microM testosterone. Area under the curve (AUC)(0- infinity ) of erythromycin with 500 microM testosterone was almost 4 times higher than AUC(0- infinity ) without any inhibitor. Rate of elimination (k(10)) for erythromycin and those with inhibitors was found to be similar (141 +/- 23 min), suggesting that elimination pathways were not altered. All the inhibitors were found to be nontoxic. Verapamil also inhibited the efflux pump with moderate change in AUC(0- infinity ) and C(max) compared with control. Thus, P-gp is found to be active in vivo, and it restricts topical erythromycin absorption across the cornea, which can be inhibited by known P-gp inhibitors. Therefore, ocular bioavailability of P-gp substrates can be significantly enhanced by proper selection of P-gp inhibitors.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Rd., Kansas City, MO 64110-2499, USA.
authors.forename: Surajit
authors.initials: S
authors.lastname: Dey
authors.forename: Sriram
authors.initials: S
authors.lastname: Gunda
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000042:Absorption / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D019540:Area Under Curve; D001692:Biological Transport; D002250:Carbon Radioisotopes; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000378:metabolism*; D003975:Diazepam / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000493:pharmacokinetics*; D005123:Eye / Q000166:cytology; D006801:Humans; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000493:pharmacokinetics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D011500:Protein Synthesis Inhibitors; D008353:Mannitol; D004917:Erythromycin; D003975:Diazepam