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...

The ATP-binding cassette (ABC) transporter breast cancer resistance protein (BCRP)/ABCG2 is a high-capacity efflux transporter with wide substrate specificity located in apical membranes of epithelia, which is involved in drug availability. BCRP is responsible for the active secretion of clinically and toxicologically important substrates to milk. The present study shows BCRP expression in sheep and cow by immunoblotting with MAb (BXP-53). Vanadate-sensitive ATPase activity with specific BCRP substrates and inhibitors was measured in bovine mammary gland homogenates. To assess the role of BCRP in ruminant mammary gland we tested the fluoroquinolone enrofloxacin (ENRO). In polarized cell lines, ENRO was transported by Bcrp1/BCRP with secretory/absorptive ratios of 6.5 and 2 respectively. The efflux was blocked by the BCRP inhibitor Ko143. ENRO pharmacokinetics in plasma and milk was studied in sheep after co-administration of drug (2.5 mg/kg, i.v.) and genistein (0.8 mg/kg, i.m.) or albendazole sulfoxide (2 mg/kg, i.v) as BCRP inhibitors. Concomitant administration of BCRP inhibitors with ENRO had no significant effect on the plasma disposition kinetics of ENRO but decreased ENRO concentrations in milk.

ABSTRACT:Methylcarbamate benzimidazoles [albendazole (ABZ), fenbendazole (FBZ), and their respective sulfoxide derivatives, albendazole sulfoxide (ABZSO) and oxfendazole (OXF)] are therapeutically important anthelmintic agents with low bioavailability. We studied their in vitro interaction with the apical ATP-binding cassette (ABC) drug efflux transporters, breast cancer resistance protein (BCRP/ ABCG2), P-glycoprotein (ABCB1), and MRP2 (ABCC2) using MD-CKII cells transduced with human MDR1, MRP2, and BCRP, and murine Bcrp1 cDNAs. These ABC drug efflux transporters extrude a wide range of xenotoxins from cells in intestine, liver, and other organs, thus affecting the bioavailability of many compounds. In transport experiments, ABZSO and OXF were transported efficiently by murine Bcrp1 and moderately by human BCRP, but not by MDR1 or MRP2. ABZ and FBZ were not found to be Bcrp1, MRP2, or P-glycoprotein substrates in vitro. OXF was found to be a good BCRP/Bcrp1 inhibitor, with somewhat higher potency in the MDCKII-BCRP cell line. The latter results were confirmed by flow cytometry experiments demonstrating inhibition by OXF of murine Bcrp1-and human BCRP-mediated mitoxantrone transport. Further studies of interactions between OXF and known BCRP/Bcrp1 substrates will be of interest. The use of efficacious BCRP/Bcrp1 inhibitors might increase the extent and duration of systemic exposure to ABZSO and OXF, with possible therapeutically beneficial effects in extra-intestinal infections.Albendazole (ABZ), fenbendazole (FBZ), and their sulfoxide derivatives (albendazole sulfoxide/ricobendazole, ABZSO; and fenbendazole-sulfoxide/oxfendazole, OXF) are methylcarbamate benzimidazoles with a broad-spectrum anthelmintic activity, widely used in human and veterinary medicine. They are used against several systemic parasitoses including nematodoses, hydatidosis, taeniasis, and others (Campbell, 1990). They are also active against various protozoa (Katiyar et al., 1994) and Grampositive bacteria (Elnima et al., 1981). ABZ is used to treat microsporidial and cryptosporidial infections, which can cause lethal diarrhea in patients treated with immunosuppressive drugs or those infected with HIV (Zulu et al., 2002;Didier et al., 2004). In addition, ABZ has shown antitumor activity (Morris et al., 2001;Pourgholami et al., 2004). Both sulfoxide derivatives (ABZSO and OXF) are the main active metabolites found in plasma after oral administration of the parent compounds, ABZ and FBZ (Lanusse and Prichard, 1993), but they are also available as commercial formulations themselves.Especially FBZ, but also ABZ, and their sulfoxides are poorly absorbed from the gastrointestinal tract (Lanusse and Prichard, 1993;Lanusse et al., 1995;Capece et al., 2000). For treatment of intestinal luminal parasites, this is ideal: intestinal concentration of the drug remains high, and there is little risk of systemic toxicity. However, for systemic treatments elsewhere in the body, substantial (systemic) uptake of the drugs is needed, and low benzimidazole bio...

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