Naslov
Interaction of macrolide antibiotics with P-glycoprotein (MDR1, ABCB1)

Autori
Munić, Vesna ; Kelnerić, Željko ; Eraković, Vesna

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
FEBS Special Meeting: ATP-Binding Cassette (ABC) Proteins: From Multidrug Resistance to Genetic Diseases, Book of Abstracts / Kuchler, Karl - Innsbruck, 2006

Skup
FEBS Special Meeting: ATP-Binding Cassette (ABC) Proteins: From Multidrug Resistance to Genetic Diseases

Mjesto i datum
Innsbruck, Austrija, 04.03.2006. - 10.03.2006

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
macrolide; P-glycoprotein

Sažetak
Macrolides are known to accumulate in cells but the exact mechanism is not fully understood. Intensity of accumulation as well as affinity for different cell types varies among macrolide compounds <I>(Bosnar M, et al., (2005) Antimicrob Agents Chemother 49, 1)</I>. Some macrolides have been reported to inhibit the function of P-glycoprotein (P-gp, MDR1, ABCB1) and some have been shown to be substrates for P-gp. The aim of our study was to compare five commonly used macrolide antibiotics (azithromycin (AZI), erythromycin (ERY), clarithromycin (CLA), roxithromycin (ROX) and telithromycin (TEL)) with respect to their ability to inhibit P-gp function, as well as to determine how P-gp affects intracellular accumulation of these macrolides. Studies were performed on P-gp overexpressing cells MES-SA/Dx5 and the parent P-gp negative cell line MES-SA. Expression of P-gp as well as of 7 other ABC transporters was analyzed by quantitative RT-PCR and Western blot. P-gp function was assessed by flow cytometric assay of rhodamine-123 (Rh123) efflux from MES-SA/Dx5 cells. Accumulation of macrolides was studied in both cell lines with verapamil used as inhibitor of P-gp. Macrolide concentrations were determined by microbiological agar diffusion method. All five tested macrolides inhibit P-gp function when Rh123 is used as P-gp substrate. CLA, ROX and TEL display a 10-20-fold higher potential to inhibit P-gp function than AZI or ERY. Since the cellular accumulation of all five tested macrolides is higher in cells without P-gp or in cells with verapamil-inhibited P-gp than in cells with functional P-gp, tested macrolides are considered to be substrates for P-gp. In contrast to our Rh123 efflux data, P-gp most strikingly influences the accumulation of AZI and ERY in cells, whereas the uptake of CLA, ROX and TEL is affected by this transporter to a lesser extent. AZI accumulates significantly better than all other tested macrolides in cells without P-gp or with impaired P-gp function, whereas in cells with functional P-gp AZI was in the range of TEL, CLA and ROX. Our results demonstrate how the expression of a single transporter can highly affect the relative affinity of the cell for structurally very similar compounds, which may at least in part explain differences in their pharmacokinetic behaviour as well as in the extent of their pharmacodynamic effects.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti

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