QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Erratum An erratum has been published All Versions of this Article: jpet.104.069583v1 311/1/246    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Dey, S. Articles by Mitra, A. K. Search for Related Content PubMed PubMed Citation Articles by Dey, S. Articles by Mitra, A. K.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Pharmacokinetics of Erythromycin in Rabbit Corneas after Single-Dose Infusion: Role of P-Glycoprotein as a Barrier to in Vivo Ocular Drug Absorption

Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri

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 [¹⁴C]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 µM testosterone. Area under the curve (AUC)_0- of erythromycin with 500 µM testosterone was almost 4 times higher than AUC_0- without any inhibitor. Rate of elimination (k₁₀) 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- 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.

Address correspondence to: Dr. Ashim K. Mitra, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Rd., Kansas City, MO 64110-2499. E-mail: mitraa{at}umkc.edu