Bioavailability of tetracyclines is substantially increased by administration of cyclosporine A, a non-specific efflux-pump blocker.

OBJECTIVES

To investigate how cyclosporine A, a nonspecific efflux-pump blocker, affects the plasma concentrations and oral bioavailability of tigecycline, oxytetracycline, chlortetracycline, doxycycline, minocycline, and tetracycline.

METHODS

Broiler chickens were used as an animal model. The tetracyclines (10 mg/kg BW) were administered intravenously, orally, and orally with cyclosporine A (50 mg/kg BW; administration: oral or intravenous). After administration, plasma samples were taken, and their concentrations of tetracyclines were measured using high-performance liquid chromatography coupled with tandem mass spectrometry. For pharmacokinetic analyses of mean plasma concentrations versus time, compartmental and non-compartmental analyses were used.

RESULTS

After oral administration of the tetracyclines, cyclosporine A administration (oral or intravenous) significantly (P < 0.05) increased the plasma concentrations, the bioavailability, the maximum plasma concentration, and the area under the curve of all the tetracyclines. Interestingly, the bioavailability of the tetracyclines was around two times higher after orally administering cyclosporine A than after intravenously administering it (P < 0.05).

CONCLUSIONS

Cyclosporine A administration increases the plasma concentrations of orally administered tetracyclines. Although cyclosporine A also inhibits renal and hepatic clearance, these results strongly suggest that efflux pumps in the intestinal epithelium are involved in the regulation of tetracycline absorption from the gastrointestinal tract.