ABSTRACT:The breast cancer resistance protein (BCRP/ABCG2) is an ATPbinding cassette drug efflux transporter that extrudes xenotoxins from cells in intestine, liver, mammary gland, and other organs, affecting the pharmacological and toxicological behavior of many compounds, including their secretion into the milk. The purpose of this study was to determine whether three widely used fluoroquinolone antibiotics (ciprofloxacin, ofloxacin, and norfloxacin) are substrates of Bcrp1/BCRP and to investigate the possible role of this transporter in the in vivo pharmacokinetic profile of these compounds and their secretion into the milk. Using polarized cell lines, we found that ciprofloxacin, ofloxacin, and norfloxacin are transported by mouse Bcrp1 and human BCRP. In vivo pharmacokinetic studies showed that the ciprofloxacin plasma concentration was more than 2-fold increased in Bcrp1 Quinolone antimicrobial drugs are widely used because of their broad spectrum and intense bactericidal activity. They are developed for oral and parenteral use in the treatment of bacterial diseases, including severe systemic infections (Brunner and Zeiler, 1988). Most quinolone antibacterial drugs are rapidly absorbed from the intestine, with a bioavailability of close to 90%, and then penetrate well into most body tissues and fluids. However, some fluoroquinolones have been reported to undergo efflux, which can explain the low bioavailability of some of them; for instance, the bioavailabilities of ciprofloxacin and norfloxacin are 50 to 80% and 30 to 40%, respectively (Sörgel et al., 1989;Lamp et al., 1992). In addition, at least 10% of i.v. administered ciprofloxacin is eliminated by intestinal secretion (Rohwedder et al., 1990). Only 1% of the dose is excreted into the bile (Parry et al., 1988). Some studies indicated that intestinal elimination of ciprofloxacin was not mediated by P-glycoprotein (ABCB1) (Griffiths et al., 1993;Cavet et al., 1997;Dautrey et al., 1999), one of the most important members of the ATP-binding cassette group of transporters, which is often involved in restricting the bioavailability of drugs. Accordingly, several groups (Lowes and Simmons, 2002;Michot et al., 2004) have recently shown that ciprofloxacin is not a substrate of this transporter or of MRP2 (ABCC2), another ABC transporter. However, the pharmacokinetics of ciprofloxacin was suggested to involve one or more active intestinal or hepatobiliary transport mechanisms in rats (Dautrey et al., 1999). Norfloxacin and ofloxacin have also been shown to be subject to active efflux (Cao et al., 1992;Rabbaa et al., 1996). Active secretory mechanisms common to all fluoroquinolones have been suggested (Griffiths et al., 1993(Griffiths et al., , 1994, as well as competition between fluoroquinolones at transporter sites (Rabbaa et al., 1996). However, the precise mechanisms involved in the pharmacokinetics of ciprofloxacin and other fluoroquinolones remain to be clarified.Several adverse effects have been reported with the use of quinolones, including nausea, diar...

Danofloxacin, a veterinary fluoroquinolone antimicrobial drug, is actively secreted into milk by an as yet unknown mechanism. One of the main determinants of active drug secretion into milk is the transporter (BCRP/ABCG2). The main purpose was to determine whether danofloxacin is an in vitro substrate for Bcrp1/BCRP and to assess its involvement in danofloxacin secretion into milk. In addition, the role of potential drug-drug interactions in this process was assessed using ivermectin. Danofloxacin was transported in vitro by Bcrp1/BCRP, and ivermectin efficiently blocked this transport. Experiments with Bcrp1(-/-) mice showed no evidence of the involvement of Bcrp1 in plasma pharmacokinetics of danofloxacin. However, the milk concentration and milk-to-plasma ratio of danofloxacin were almost twofold higher in wild-type compared with Bcrp1(-/-) mice. The in vivo interaction with ivermectin was studied in sheep after co-administration of danofloxacin (1.25 mg/kg, i.m.) and ivermectin (0.2 mg/kg, s.c.). Ivermectin had no significant effect on the plasma levels of danofloxacin but significantly decreased danofloxacin concentrations in milk by almost 40%. Concomitant administration of multiple drugs, often used in veterinary therapy, may not only affect their pharmacological activity but also their secretion into milk, because of potential drug-drug interactions mediated by BCRP.

No abstract

In commercial dairy production, the risk of drug residues and environmental pollutants in milk from ruminants has become an outstanding problem. One of the main determinants of active drug secretion into milk is the ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP). It is located in several organs associated with drug absorption, metabolism, and excretion, and its expression is highly induced during lactation in the mammary gland of ruminants, mice, and humans. As a consequence, potential contamination of milk could expose suckling infants to xenotoxins. In cows, a SNP for this protein affecting quality and quantity of milk production has been described previously (Y581S). In this study, our main purpose was to determine whether this polymorphism has an effect on transcellular transport of veterinary drugs because this could alter substrate pharmacokinetics and milk residues. We stably expressed the wild-type bovine ABCG2 and the Y581S variant in Madin-Darby canine kidney epithelial cells (MDCKII) and MEF3.8 cell lines generating cell models in which the functionality of the bovine transporter could be addressed. Functional studies confirmed the greater functional activity in mitoxantrone accumulation assays for the Y581S variant with a greater relative V(MAX) value (P = 0.040) and showed for the first time that the Y581S variant presents greater transcellular transport of the model ABCG2 substrate nitrofurantoin (P = 0.024) and of 3 veterinary antibiotics, the fluoroquinolone agents enrofloxacin (P = 0.035), danofloxacin (P = 0.001), and difloxacin (P = 0.008), identified as new substrates of the bovine ABCG2. In addition, the inhibitory effect of the macrocyclic lactone ivermectin on the activity of wild-type bovine ABCG2 and the Y581S variant was also confirmed, showing a greater inhibitory potency on the wild-type protein at all the concentrations tested (5 μM, P = 0.017; 10 μM, P = 0.001; 25 μM, P = 0.008; and 50 μM, P = 0.003). Differential transport activity depending on the genotype together with the differential inhibition pattern might have clinical consequences, including changes in substrate pharmacokinetics (and subsequently pharmacodynamics) and more specifically, changes in secretion of ABCG2 substrates into milk, potentially implying important consequences to veterinary therapeutics.

No abstract