Danofloxacin‐mesylate is a substrate for ATP‐dependent efflux transporters

Abstract

Background and purpose: Next to its broad antimicrobial spectrum, the therapeutic advantages of the fluoroquinolone antimicrobial drug Danofloxacin-Mesylate (DM) are attributed to its rapid distribution to the major target tissues such as lungs, intestines and the mammary gland in animals. Previous analyses revealed that effective drug concentrations are achieved also in luminal compartments of these organs, suggesting that active transport proteins facilitate excretion into the luminal space. Members of the ATP-Binding Cassette (ABC) superfamily, including P-gp, BCRP and MRP2 are known to be expressed in many tissue barriers and in cell-membranes facing luminal compartments. Hence we hypothesized that DM is a substrate for one of these efflux-transporters. Experimental approach: Confluent monolayers of Caco-2 cells, grown on microporous membranes in two-chamber devices were used. DM concentrations were measured by fluorimetric assay after HPLC of the culture media. Key results: DM transport across Caco-2 cells was asymmetric, with a rate of secretion exceeding that of absorption. The P-gp inhibitors PSC833 and GF120918 and the MRP-inhibitor MK571 partially decreased the secretion of DM and increased its absorption rate. The BCRP inhibitor, Ko143, decreased secretion only at a concentration of 1 mM. When DM was applied together with ciprofloxacin, secretion as well as absorption of DM decreased. Conclusions and Implications: DM is a substrate for the efflux transporters P-gp and MRP2, whereas the specific role of BCRP in DM transport needs further evaluation. These findings provide a mechanistic basis for the understanding of the pharmacokinetics of DM in healthy and diseased individuals.

Concentrations of danofloxacin 18% solution in plasma, milk and tissues after subcutaneous injection in dairy cows

“…As a result of its high lipid solubility, low protein binding (13%) [30], and ATP-dependent efflux transporters [35], danofloxacin in this study presented a very high volume of distribution (Vd ss = 5.79 L kg −1 ). This large Vd may also be attributed to high intracellular penetration of the administered compound.…”

Age-Related P-Glycoprotein Expression in the Intestine and Affecting the Pharmacokinetics of Orally Administered Enrofloxacin in Broilers

“…Fluoroquinolones have been successfully used for the treatment of colibacillosis and mycoplasma infection in poultry [19,20]. Some of them, such as danofloxacin and gatifloxacin, have proven to be the substrates for ABC transporters [21,22,23,24]. Enrofloxacin is also one of the most extensively used therapeutic agents in poultry.…”

Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: interaction with ivermectin

“…The main pharmacological consequence is that contamination of milk exposes suckling infants and dairy consumers to xenotoxins (van Herwaarden & Schinkel, 2006). Two other ABC transporters, P‐glycoprotein and MRP2, have been shown to interact with danofloxacin (Schrickx & Fink‐Gremmels, 2007). However, these two proteins are not substantially expressed or induced in the lactating mammary gland (van Herwaarden & Schinkel, 2006).…”

“…However, these two proteins are not substantially expressed or induced in the lactating mammary gland (van Herwaarden & Schinkel, 2006). Moreover, the interaction of BCRP, the best candidate for milk secretion, with danofloxacin transport remains elusive (Schrickx & Fink‐Gremmels, 2007).…”