Human ABC transporters ABCG2 (BCRP) and ABCG4

Koshiba, S.; An, Rong; Saito, Hikaru; Wakabayashi, Kunihiko; Tamura, Ai; Ishikawa, Toshihisa

doi:10.1080/00498250801986944

Cited by 42 publications

(21 citation statements)

References 111 publications

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“…This is because drug transporters in cancer cells can prevent the entry of therapeutic drugs that are "harmful" to these cancer cells and/or pump "harmful" chemotherapeutic drugs out of cells (i.e., eliminating therapeutic drugs from a growing tumor) (Leslie et al, 2005;Löscher and Potschka, 2005;Miller et al, 2008;Poguntke et al, 2010;Robey et al, 2010;Shukla et al, 2011). Subsequent studies have shown that normal cells and tissues, such as the brain, liver, and testes (including Sertoli cells) and different germ cells (including spermatogonia, spermatocytes, developing spermatids) express high levels of different drug transporters (Leslie et al, 2005;Löscher and Potschka, 2005;Koshiba et al, 2008;Setchell, 2008;He et al, 2009;Su et al, 2011a). Besides drugs (e.g., male contraceptives), cations, anions, electrolytes, steroids (e.g., corticosteroids), small biomolecules, and even xenobiotics, toxicants and certain sex hormones (e.g., estrogens, androgens) can enter or be eliminated from a cell (e.g., Sertoli cell) via drug transporters (Löscher and Potschka, 2005;Cérec et al, 2007;Koshiba et al, 2008;Setchell, 2008;Su et al, 2011a), illustrating their significance in conferring a unique microenvironment in the apical compartment behind the BTB for meiosis and postmeiotic spermatid development during spermiogenesis.…”

Section: B Background and Classification Of Drug Transporters Theirmentioning

confidence: 99%

The Blood-Testis Barrier and Its Implications for Male Contraception

2011

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Section: B Background and Classification Of Drug Transporters Theirmentioning

confidence: 99%

The Blood-Testis Barrier and Its Implications for Male Contraception

2011

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“…Several members of this family are primary drug transporters that pump substrates out of cells by using ATP as the energy source, thus significantly modulating the absorption, distribution, metabolism, and elimination of endogenous compounds, drugs, and other xenobiotics (Leslie et al, 2005;Xia et al, 2005a;Shitara et al, 2006;Koshiba et al, 2008;Zhou, 2008;Giacomini et al, 2010). Permeability glycoprotein (P-gp; encoded by multiple drug resistance protein 1, ABCB1), a member of the ABC transporter superfamily, is expressed in the human intestine, liver, brain, and other tissues, and plays an important role in oral bioavailability and tissue distribution of drug molecules that are substrates for this transporter (Zhou 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The breast cancer resistance protein (BCRP, ABCG2), another ATPbinding cassette efflux drug transporter (Doyle and Ross, 2003;Mao and Unadkat, 2005;Krishnamurthy and Schuetz, 2006), is highly expressed in various normal tissues, such as placenta, small intestine, liver, and mammary glands (Maliepaard et al, 2001). BCRP can transport a broad spectrum of substrates, including chemotherapeutic agents, organic anions, and xenobiotics (Doyle and Ross, 2003;Mao and Unadkat, 2005), and plays an important role in drug disposition (Koshiba et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Efflux Transporters Involved in Distribution and Disposition of Apixaban

et al. 2013

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The studies reported here were conducted to investigate the transport characteristics of apixaban (1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo [3,4-c]pyridine-3-carboxamide) and to understand the impact of transporters on apixaban distribution and disposition. In human permeability glycoprotein (P-gp)-and breast cancer resistance protein (BCRP)-cDNA-transfected cell monolayers as well as Caco-2 cell monolayers, the apparent efflux ratio of basolateral-to-apical (Pc B-A ) versus apical-to-basolateral permeability (Pc A-B ) of apixaban was >10. The P-gp-and BCRP-facilitated transport of apixaban was concentration-and time-dependent and did not show saturation over a wide range of concentrations (1-100 mM). The efflux transport of apixaban was also demonstrated by the lower mucosal-to-serosal permeability than that of the serosal-tomucosal direction in isolated rat jejunum segments. Apixaban did not inhibit digoxin transport in Caco-2 cells. Ketoconazole decreased the P-gp-mediated apixaban efflux in Caco-2 and the P-gp-cDNA-transfected cell monolayers, but did not affect the apixaban efflux to a meaningful extent in the BCRP-cDNA-transfected cell monolayers. Coincubation of a P-gp inhibitor (ketoconazole or cyclosporin A) and a BCRP inhibitor (Ko134) provided more complete inhibition of apixaban efflux in Caco-2 cells than separate inhibition by individual inhibitors. Naproxen inhibited apixaban efflux in Caco-2 cells but showed only a minimal effect on apixaban transport in the BCRP-transfected cells. Naproxen was the first nonsteroidal antiinflammatory drug that was demonstrated as a weak P-gp inhibitor. These results demonstrate that apixaban is a substrate for efflux transporters P-gp and BCRP, which can help explain its low brain penetration, and low fetal exposures and high milk excretion in rats.

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“…Drug transporters and drug-metabolizing enzymes are heterogeneously expressed in the intestine, affecting drug absorption and bioavailability (Suzuki and Sugiyama, 2000;Kaminsky and Zhang, 2003;Paine et al, 2006). P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2), two members of the ABC transporter superfamily, are highly expressed at the lumenal brush border membranes of intestinal enterocytes, proximal tubular membranes in the kidney, and canalicular membranes of hepatocytes in the liver and play an important role in drug absorption, tissue distribution, and drug elimination (Maliepaard et al, 2001;Doyle and Ross, 2003;Unadkat et al, 2004;Mao and Unadkat, 2005;Krishnamurthy and Schuetz, 2006;Huls et al, 2008;Koshiba et al, 2008;Zhou, 2008;Vlaming et al, 2009;Giacomini et al, 2010). In human, the MDR1 (P-gp) gene encodes a single drug transporting P-gp, where in mice and rats, the mdr1a and mdr1b genes encode two P-glycoprotein isoforms, but mdr1b is not expressed in mouse intestine (Thiebaut et al, 1987;Schinkel et al, 1994).…”

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confidence: 99%

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

Zhang

Frost

et al. 2013

Drug Metab Dispos

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The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile ductcannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.

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Human ABC transporters ABCG2 (BCRP) and ABCG4

Cited by 42 publications

References 111 publications

The Blood-Testis Barrier and Its Implications for Male Contraception

The Blood-Testis Barrier and Its Implications for Male Contraception

Characterization of Efflux Transporters Involved in Distribution and Disposition of Apixaban

Investigating the Enteroenteric Recirculation of Apixaban, a Factor Xa Inhibitor: Administration of Activated Charcoal to Bile Duct-Cannulated Rats and Dogs Receiving an Intravenous Dose and Use of Drug Transporter Knockout Rats

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