Breast Cancer Resistance Protein (Bcrp/Abcg2) Transports Fluoroquinolone Antibiotics and Affects Their Oral Availability, Pharmacokinetics, and Milk Secretion

Abstract

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...

ATP-binding cassette, subfamily G (ABCG family)

“…ABCG2 expression is highly induced in the apical membrane of alveolar epithelial cells during late pregnancy and especially during lactation [30], and is involved in the secretion of drugs into milk. The milk-toplasma concentration ratio of topotecan [30], PhIP [30], acyclovir [30], nitrofurantoin [51], and ciprofloxacin [52] was markedly reduced in Abcg2 knockout mice, but not that of DHEAS and folate [30].…”

“…For drugs, it has also been shown that BCRP limits the oral absorption of topotecan [29], salfasalzine [86], and ciprofloxacin [52]. Abcg2 has been shown to account for the efflux of intracellularly formed glucuronide and sulfate conjugates (E3040 glucuronide, E3040 sulfate, and 4-methylumbelliferone sulfate) [1]; the active form of the ester-type prodrug of ME3277 [38] in the small intestine; the biliary excretion of drugs such as nitrofurantoin [51], methotrexate [10], pitavastatin [25], and salfasalazine [86]; and the urinary excretion of methotrexate [10] and E3040 sulfate [56].…”

“…The mutants acquire the ability to carry out efflux transport of anthracylcines and rhodamine 123 [26], but lose the ability to transport methotrexate [54]. In addition to anticancer drugs, cumulative studies have demonstrated the broad substrate specificity of ABCG2, and it accepts a variety of drugs [10,25,30,52,51,86], endogenous compounds, sulfate conjugates [1, 56,72], and carcinogens [75,76] as substrate. For investigating functional activity of ABCG2, potent inhibitors of BCRP have been reported, which include fumitremorgin C [61] [69], and imatinib (Gleevec) [59].…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…Chenodeoxycholate-3-sulfate [15] 131 Glycodeoxycholate [15] 2.0 Glycoursodeoxycholate [15] 4.1 Cholate [15,54] [15,54] 7.3/13 Deoxycholate [15,54] 5.2-13 Glycochenodeoxycholate [54] 2.0/2.9 Glychodeoxycholate [54] 2.4/5.4 Glycholate [54] 11/21 Taurochenodeoxycholate [15,54] 1.0-6.1 Taurocholate [15,54] 7.3-25 Taurodeoxycholate [15] 4.5-17 Taurourosdeoxycholate [15] 28 Ursodeoxycholate [15,54] 36 [60] Estrone [56] Bisantrene [67] Betamethasone [57] Riboflavin [68] Taurolithocholate sulfate [56] 37 a Cerivastatin [61] Cerivastain [61] 18 Uric acid [69] Vitamin K3 [ [70] Ciprofloxacin [71] Daunorubicin [56] 59 a Daunorubicin [67] Dexamethasone [57] Diclofenac [72] Diclofenac [72] 71-78 Dipyridamole [73] Digoxin [57] Doxorubicin [67,74] Dipyridamole [73] 6.4 a Enrofloxacin [75] Doxorubicin [56,76] Epirubicin [67] Fluvastatin [61] 5.4 Fluvastatin [61,62] Glibenclamide [77] 150 a Glibenclamide …”

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

“…ABCG2 mRNA expression was higher compared to other efflux transporter in the human small intestine, which is a rate-limiting barrier to oral drug absorption [64] . The important impact of ABCG2 on the intestinal absorption was further supported by several knockout mice research, which have indicated that ABCG2 affects the pharmacological and toxicological behavior of many drugs [65][66][67] . Also, polymorphisms might influence the role of ABCG2 in intestinal absorption.…”