NDLI: Carrier Mechanisms Involved in the Transepithelial Transport of bis(POM)-PMEA and Its Metabolites Across Caco-2 Monolayers

Content Provider	Springer Nature Link
Author	Annaert, P. Van Gelder, J. Naesens, L. De Clercq, E. Van den Mooter, G. Kinget, R. Augustijns, P.
Copyright Year	1998
Abstract	Purpose. To investigate the role of carrier mechanisms in: [1] the polarized transport of the bis(pivaloyloxymethyl)- [bis(POM)-] ester prodrug of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine [PMEA] and [2] the directional secretion of its metabolites. Methods. Caco-2 monolayers were used to study the modulating effect of carriers on the transport of bis(POM)-PMEA and the efflux of intracellularly formed metabolites mono(POM)-PMEA and PMEA from the cells. The interaction of bis(POM)-PMEA and its metabolites with the efflux mechanisms present in Caco-2 monolayers was investigated by testing the effect of various concentrations of verapamil (30, 100, 300 μM) or indomethacin (10-500 μM) on transport and efflux. Results. Polarity in transport of bis(POM)-PMEA (50 μM) across Caco-2 monolayers was noted: transport of total PMEA [=bis(POM)-PMEA, mono(POM)-PMEA and PMEA] was significantly higher in basolateral (BL) to apical (AP) direction (14.5 ± 0.4%) than transport in the opposite (AP to BL) direction (1.7 ± 0.2%). This difference was reduced in a concentration dependent way when verapamil (0−100 μM) was included in both AP and BL incubation media. After loading the cells with bis(POM)-PMEA (100 μM) for 1 hr, studies on efflux of PMEA and mono(POM)-PMEA from the Caco-2 monolayers over a 3 hr period, revealed that both metabolites were preferentially secreted towards the AP compartment. Efflux of PMEA towards AP and BL compartments amounted to 14.6 ± 1.1 % and 5.3 ± 0.4%, respectively, of the initial intracellular amount of total PMEA, while efflux of mono(POM)-PMEA towards AP and BL compartments was limited to 2.3 ± 0.1 % and 0.5 ± 0.1 %, respectively. When 10 μM indomethacin was included in the AP incubation medium, efflux of PMEA was decreased to 7.8 ± 0.3% and 3.3 ± 0.3% towards the AP and BL compartments, respectively. The decrease in efflux by indomethacin was concentration-dependent up to 100 μM. Transepithelial transport of total PMEA was also reduced in the presence of 30 μM indomethacin, as reflected in smaller concentrations of PMEA and mono(POM)-PMEA in the acceptor compartment, irrespective of the transport direction. Conclusions. The data obtained in this study suggest that bis(POM)-PMEA is substrate for a P-glycoprotein-like carrier mechanism in Caco-2 monolayers, while its metabolites mono(POM)-PMEA and PMEA are transported by a non-P-glycoprotein efflux protein.
Starting Page	1168
Ending Page	1173
Page Count	6
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	15
Issue Number	8
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	1998-01-01
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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