Intestinal Ciprofloxacin Efflux: The Role of Breast Cancer Resistance Protein (ABCG2)

Haslam, Iain S.; Wright, Jamie A.; O’Reilly, Derek; Sherlock, David; Coleman, Tanya; Simmons, Nicholas L.

doi:10.1124/dmd.111.038323

Cited by 52 publications

(32 citation statements)

References 42 publications

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“…Moreover, the decrease in darunavir excretion upon coadministration of zosuquidar was strongest in distal loops. These regional differences were in accordance with the reported literature, demonstrating an increase in P-gp expression from proximal to distal sites of the small intestine in rats (Haslam et al, 2011;MacLean et al, 2008;Takara et al, 2003). Nevertheless, despite reported lower expression of P-gp at these proximal intestinal sites, excretion of darunavir was still substantial.…”

Section: Darunavir: Intravenous Infusionsupporting

confidence: 94%

Hepatobiliary and intestinal elimination of darunavir in an integrated preclinical rat model

Stappaerts¹,

Fattah²,

Annaert³

et al. 2013

Xenobiotica

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1. Although valuable in vitro models exist to study drug elimination from the systemic circulation, more integrated models may improve mechanistic insight in a biorelevant setting. 2. This study aimed to explore (1) intestinal and biliary excretion of the HIV protease inhibitor darunavir and its impact on systemic disposition and (2) to evaluate to what extent findings in an in situ excretion model in rat can be captured by individual in vitro models. 3. Contemporary in vitro models were applied to study intestinal and hepatobiliary disposition of darunavir and data were compared with findings in the in situ excretion model. 4. Both in situ and in vitro experiments demonstrated significant metabolism of darunavir, which could be strongly inhibited by the P450 inhibitor 1-aminobenzotriazole. Using the P-gp inhibitor zosuquidar, P-gp mediated excretion of darunavir from blood towards gastrointestinal lumen was evidenced and this was confirmed by transport studies in Caco-2 cells. Moreover, involvement of P-gp in the biliary excretion of darunavir was also demonstrated in situ. 5. In general, in situ findings corresponded well with in vitro data. The in situ excretion model offers the possibility to gain mechanistic insight in intestinal and hepatobiliary excretion processes and, at the same time, evaluate their impact on the systemic disposition of a compound.

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Section: Darunavir: Intravenous Infusionsupporting

confidence: 94%

Hepatobiliary and intestinal elimination of darunavir in an integrated preclinical rat model

Stappaerts¹,

Fattah²,

Annaert³

et al. 2013

Xenobiotica

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“…ABCG2, a member of the ATP-binding cassette G2 subfamily, is a gene that promotes oral cancer development and multidrug resistance when it is overexpressed in tumour cells [38,39,40]. In addition, NANOG is a member of the homeobox family of DNA binding transcription factors that plays an important role in the maintenance of pluripotency and in the self-renewal of human embryonic stem cells [41].…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of Stem Cell Markers in Human Adamantinomatous Craniopharyngioma and Pituitary Adenoma

Chang¹,

Araujo²,

Cirqueira³

et al. 2016

Neuroendocrinology

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Background/Aims: Although craniopharyngioma (CP) is histologically benign, it is a pituitary tumour that grows rapidly and often recurs. Adamantinomatous CP (ACP) was associated with an activating mutation in β-catenin, and it has been postulated that pituitary stem cells might play a role in oncogenesis in human ACP. Stem cells have also been identified in pituitary adenoma. Our aim was to characterize the expression pattern of ABCG2, CD44, DLL4, NANOG, NOTCH2, POU5F1/OCT4, SOX2, and SOX9 stem cell markers in human ACP and pituitary adenoma. Methods and Results: We studied 33 patients (9 ACP and 24 adenoma) using real-time quantitative PCR (RT-qPCR) and immunohistochemistry. SOX9 was up-regulated in ACP, exhibiting positive immunostaining in the epithelium and stroma, with the highest expression in patients with recurrence. CD44 was overexpressed in ACP as confirmed by immunohistochemistry. SOX2 did not significantly differ among the tumour types. The RT-qPCR array showed an increased expression of MKI67,OCT4/POU5F1, and DLL4 in all tumours. NANOG was decreased in ACP. ABCG2 was down-regulated in most of the tumours. NOTCH2 was significantly decreased in the adenomas. Conclusion: Our results confirm the presence of stem cell markers in human pituitary tumours as well as the different expression patterns of ACP and adenoma. These findings suggest that ACP may originate from a more undifferentiated cell cluster. Additionally, SOX9 immunodetection in the stroma and the highest expression levels related to the relapse of patients suggest a contribution to the aggressive behaviour and high recurrence of this tumour type.

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“…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). The expression of intestinal efflux transporters is region dependent, with the expression of P-gp generally reported to increase from proximal duodenum to distal ileum in rats and humans (Mouly and Paine, 2003;Englund et al, 2006;Berggren et al, 2007;Hilgendorf et al, 2007;MacLean et al, 2008;Haslam et al, 2011). Both BCRP expression and its efflux function reached to peak in the ileum in rat and mouse intestines (Enokizono et al, 2007;Haslam et al, 2011); however, BCRP appeared to have the greatest expression in the duodenum along the human gastrointestinal tract (Gutmann et al, 2005).…”

mentioning

confidence: 99%

“…The expression of intestinal efflux transporters is region dependent, with the expression of P-gp generally reported to increase from proximal duodenum to distal ileum in rats and humans (Mouly and Paine, 2003;Englund et al, 2006;Berggren et al, 2007;Hilgendorf et al, 2007;MacLean et al, 2008;Haslam et al, 2011). Both BCRP expression and its efflux function reached to peak in the ileum in rat and mouse intestines (Enokizono et al, 2007;Haslam et al, 2011); however, BCRP appeared to have the greatest expression in the duodenum along the human gastrointestinal tract (Gutmann et al, 2005). The expression of P-gp and BCRP is organ and species dependent, with a lower expression of BCRP in the kidney of human than rat and a higher expression of BCRP than P-gp in human intestines (Taipalensuu et al, 2001).…”

mentioning

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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Intestinal Ciprofloxacin Efflux: The Role of Breast Cancer Resistance Protein (ABCG2)

Cited by 52 publications

References 42 publications

Hepatobiliary and intestinal elimination of darunavir in an integrated preclinical rat model

Hepatobiliary and intestinal elimination of darunavir in an integrated preclinical rat model

Differential Expression of Stem Cell Markers in Human Adamantinomatous Craniopharyngioma and Pituitary Adenoma

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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