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Dive into the research topics where Gracia Merino is active.

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Featured researches published by Gracia Merino.


Molecular and Cellular Biology | 2007

Multidrug Transporter ABCG2/Breast Cancer Resistance Protein Secretes Riboflavin (Vitamin B2) into Milk

Antonius E. van Herwaarden; Els Wagenaar; Gracia Merino; Johan W. Jonker; Hilde Rosing; Jos H. Beijnen; Alfred H. Schinkel

ABSTRACT The multidrug transporter breast cancer resistance protein (BCRP/ABCG2) is strongly induced in the mammary gland during pregnancy and lactation. We here demonstrate that BCRP is responsible for pumping riboflavin (vitamin B2) into milk, thus supplying the young with this important nutrient. In Bcrp1−/− mice, milk secretion of riboflavin was reduced >60-fold compared to that in wild-type mice. Yet, under laboratory conditions, Bcrp1−/− pups showed no riboflavin deficiency due to concomitant milk secretion of its cofactor flavin adenine dinucleotide, which was not affected. Thus, two independent secretion mechanisms supply vitamin B2 equivalents to milk. BCRP is the first active riboflavin efflux transporter identified in mammals and the first transporter shown to concentrate a vitamin into milk. BCRP activity elsewhere in the body protects against xenotoxins by reducing their absorption and mediating their excretion. Indeed, Bcrp1 activity increased excretion of riboflavin into the intestine and decreased its systemic availability in adult mice. Surprisingly, the paradoxical dual utilization of BCRP as a xenotoxin and a riboflavin pump is evolutionarily conserved among mammals as diverse as mice and humans. This study establishes the principle that an ABC transporter can transport a vitamin into milk and raises the possibility that other vitamins and nutrients are likewise secreted into milk by ABC transporters.


Drug Metabolism and Disposition | 2006

BREAST CANCER RESISTANCE PROTEIN (BCRP/ABCG2) TRANSPORTS FLUOROQUINOLONE ANTIBIOTICS AND AFFECTS THEIR ORAL AVAILABILITY, PHARMACOKINETICS, AND MILK SECRETION

Gracia Merino; Ana I. Alvarez; Mivis M. Pulido; Antonio J. Molina; Alfred H. Schinkel; Julio G. Prieto

The breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding 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–/– compared with wild-type mice (1.77 ± 0.73 versus 0.85 ± 0.39 μg/ml, p < 0.01) after oral administration of ciprofloxacin (10 mg/kg). The area under the plasma concentration-time curve in Bcrp1–/– mice was 1.5-fold higher than that in wild-type mice (48.63 ± 5.66 versus 33.10 ± 4.68 min · μg/ml, p < 0.05) after i.v. administration (10 mg/kg). The milk concentration and milk/plasma ratio of ciprofloxacin were 2-fold higher in wild-type than in Bcrp1–/– lactating mice. We conclude that Bcrp1 is one of the determinants for the bioavailability of fluoroquinolones and their secretion into the milk.


Journal of Pharmaceutical Sciences | 2010

Modulation of the activity of ABC transporters (P-glycoprotein, MRP2, BCRP) by flavonoids and drug response

Ana I. Alvarez; Rebeca Real; Miriam Perez; Gracia Mendoza; Julio G. Prieto; Gracia Merino

The present article aims to review the up-to-date information on the most recent studies of the interaction of flavonoids with ABC transporters, in particular the drug pharmacokinetic consequences of such a relationship. In addition, the modulation of the expression of the ABC transporters by flavonoids is also illustrated. Flavonoids are a large group of plant polyphenols present extensively in our daily diets and herbal products. High intake of isoflavones has been associated with a variety of beneficial effects on several common diseases. These polyphenols interact with ABC drug transporters involved in drug resistance and drug absorption, distribution and excretion. A number of studies have demonstrated inhibition of drug transporters by flavonoids. This flavonoid-ABC-transporter interaction could be beneficial for poorly absorbed drugs but could also result in severe drug intoxication, especially drugs with a narrow therapeutic window. On the other hand, flavonoids are themselves substrates of ABC transporters. These proteins can affect the oral availability and tissue distribution of these compounds, modifying their beneficial effects. The challenge is to find a suitable way to predict harmful drug-flavonoid interactions mediated by these transporters.


Drug Metabolism and Disposition | 2007

Involvement of breast cancer resistance protein (ABCG2) in the biliary excretion mechanism of fluoroquinolones.

Tomohiro Ando; Hiroyuki Kusuhara; Gracia Merino; Ana I. Alvarez; Alfred H. Schinkel; Yuichi Sugiyama

Fluoroquinolones are effective antibiotics for the treatment of bile duct infections. It has been shown that the biliary excretion of grepafloxacin is partly accounted for by multidrug resistance-associated protein 2 (MRP2/ABCC2), whereas neither MRP2 nor P-glycoprotein is involved in the biliary excretion of ulifloxacin. In the present study, we examined the involvement of breast cancer resistance protein (BCRP/ABCG2) in the biliary excretion of fluoroquinolones (grepafloxacin, ulifloxacin, ciprofloxacin, and ofloxacin). In Madin-Darby canine kidney II cells expressing human BCRP or mouse Bcrp, the basal-to-apical transport of grepafloxacin and ulifloxacin was greater than that of the mock control, which was inhibited by a BCRP inhibitor, 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143). Plasma and bile concentrations of fluoroquinolones were determined in wild-type and Bcrp(-/-) mice after i.v. bolus injection. The cumulative biliary excretion of fluoroquinolones was significantly reduced in Bcrp(-/-) mice, resulting in a reduction of the biliary excretion clearances to 86, 50, 40, and 16 of the control values, for ciprofloxacin, grepafloxacin, ofloxacin, and ulifloxacin, respectively. Preinfusion of sulfobromophthalein significantly inhibited the biliary excretion of grepafloxacin in Bcrp(-/-) mice. There was no change in the tissue/plasma concentration ratios of fluoroquinolones in the liver or brain, whereas those in the kidney were increased 3.6- and 1.5-fold for ciprofloxacin and grepafloxacin, respectively, in Bcrp(-/-) mice but were unchanged for ofloxacin and ulifloxacin. The present study shows that BCRP mediates the biliary excretion of fluoroquinolones and suggests that it is also involved in the tubular secretion of ciprofloxacin and grepafloxacin.


Journal of Pharmaceutical Sciences | 2008

Fluoroquinolone Efflux Mediated by ABC Transporters

Ana I. Alvarez; Miriam Perez; Julio G. Prieto; Antonio J. Molina; Rebeca Real; Gracia Merino

Quinolones and fluoroquinolones are broad spectrum bactericidal drugs, which are widely used in both human and veterinary medicine. These drugs can quite easily enter cells and are often used to treat intracellular pathogens. Some fluoroquinolones have been reported to undergo efflux, which could explain their low bioavailability. There is a growing need to understand resistance mechanisms to quinolones, involving for instance mutations or the action of efflux pumps. Several members of the ATP-binding cassette (ABC) drug efflux transporter family (MDR, MRP, ABCG2) significantly affect the pharmacokinetic disposition of quinolones. Active secretory mechanisms common to all fluoroquinolones have been suggested, as well as competition between fluoroquinolones at transporter sites. For grepafloxacin and its metabolites, MRP2 has been demonstrated to mediate biliary excretion. However, MDR1 is responsible for grepafloxacin intestinal secretion. Recently it has been shown that ciprofloxacin and enrofloxacin are efficiently transported ABCG2 substrates which are actively secreted into milk. It appears that multiple ABC transporters contribute to the overall secretion of fluoroquinolones. The objective of this work is to review the recent advances in insights into ABC transporters and their effects on fluoroquinolone disposition and resistance including data on drug secretion into milk.


Comparative Biochemistry and Physiology C-toxicology & Pharmacology | 2001

Protective effects of Panax ginseng on muscle injury and inflammation after eccentric exercise

Antonio C Cabral de Oliveira; Andrea de Castro Perez; Gracia Merino; Julio G. Prieto; Ana I. Alvarez

Eccentric muscle contraction causes fibre injury associated with disruption of the myofibrillar cytoskeleton. The medicinal plant Panax ginseng C.A. Meyer, known for its therapeutic properties, was studied to explore its protective effects after eccentric contraction. A crude extract and a standardised extract (G115) of different saponin compositions were tested as to their efficacy in reducing lipid peroxidation, inflammation and release of myocellular proteins after the realisation of an eccentric contraction protocol on a rat treadmill. Plasma creatine kinase (CK) levels were significantly reduced by approximately 25% after ingestion of both extracts of ginseng. Both extracts reduced lipid peroxidation by approximately 15% as measured by malondialdehyde levels. beta-Glucuronidase concentrations and glucose-6-phosphate dehydrogenase (G6PDH) levels, which can be considered markers of inflammation, were also significantly reduced. The values of beta-glucuronidase were increased from 35.9+/-1.5 to 128.4+/-8.1 in vastus and to 131.1+/-12.1 U x g(-1) in rectus, the protection due to ginseng administration being approximately 40% in both muscles. Both extracts appeared to be equally effective in reducing injuries and inflammation caused by eccentric muscle contractions.


International Journal of Pharmaceutics | 2003

Intestinal elimination of albendazole sulfoxide: pharmacokinetic effects of inhibitors.

Gracia Merino; Antonio J. Molina; José L. Garcı́a; Mivis M. Pulido; Julio G. Prieto; Ana I. Alvarez

Albendazole (ABZ) is an anthelmintic drug widely used in human and veterinary medicine. Intestinal and hepatic ABZ metabolism leads to albendazole sulfoxide (ABZSO), the active metabolite. This work examines the mechanism involved in intestinal elimination of ABZSO and their pharmacokinetic consequences in rat and sheep. To assess the drug intestinal elimination, an upper small intestine segment was isolated and perfused in situ with saline, after ABZSO administration (10 mg/kg i.v.). The intestinal clearance of ABZSO was 0.106+/-0.010 ml/min, exhibiting a stereoselective intestinal elimination to (-)ABZSO form. Oxfendazole, ampicillin and cyclosporine significantly reduced the intestinal elimination of ABZSO to 0.079+/-0.008, 0.069+/-0.009 and 0.065+/-0.012 ml/min, respectively. Glucose significantly induced ABZSO intestinal elimination. Pharmacokinetic results showed a clear and statistically significant interaction between ABZ metabolites and drug efflux inhibitors. In rat, an increased area under the curve (AUC) for ABZSO in the groups co-administered with ABZ plus verapamil (43%) and plus ketoconazole (29%) was obtained. In sheep, the AUC for ABZSO in the groups co-administered with the inhibitors were significantly higher 53.68% with verapamil, 78.62% with quinidine, and 50.55% with ivermectin.


Journal of Agricultural and Food Chemistry | 2010

Involvement of Breast Cancer Resistance Protein (BCRP1/ABCG2) in the Bioavailability and Tissue Distribution of trans-Resveratrol in Knockout Mice

Irene Alfaras; Miriam Perez; Maria Emília Juan; Gracia Merino; Julio G. Prieto; Joana M. Planas; Ana I. Alvarez

trans-Resveratrol undergoes extensive metabolism in the intestinal cells, which leads to the formation of glucuronide and sulfate conjugates. Given the important role of the breast cancer resistance protein (ABCG2/BCRP) in the efflux of conjugated forms, the present study investigates the bioavailability and tissue distribution of trans-resveratrol and its metabolites after the oral administration of 60 mg/kg in Bcrp1(-/-) mice. trans-Resveratrol and its metabolites were measured in intestinal content, plasma and tissues by HPLC. At 30 min after administration, intestinal content showed decreases of 71% and 97% of resveratrol glucuronide and sulfate, respectively, in Bcrp1(-/-), indicating a lower efflux from the enterocytes. Furthermore, the area under plasma concentration curves (AUC) of these metabolites increased by 34% and 392%, respectively, whereas a decrease in the AUC of trans-resveratrol was found. In conclusion, Bcrp1 plays an important role in the efflux of resveratrol conjugates, contributing to their bioavailability, tissue distribution and elimination.


Chemico-Biological Interactions | 2009

In vitro and in vivo interaction of moxidectin with BCRP/ABCG2.

Miriam Perez; Alba G. Blazquez; Rebeca Real; Gracia Mendoza; Julio G. Prieto; Gracia Merino; Ana I. Alvarez

The study characterizes the interaction between BCRP/ABCG2 and moxidectin by means of cellular transport, and pharmacokinetic studies in Bcrp1 (-/-) and wild-type mice. Milbemycin moxidectin ([(3)H]-moxidectin) was tested for its ability to be transported across MCDK-II epithelial monolayer cultures transfected with BCRP. In a second approach, accumulation assays by BCRP-expressing Xenopus laevis oocytes were carried out. Finally, pharmacokinetic studies were performed in order to establish the role of the transporter in milk secretion and tissue distribution. The efflux was negligible in polarized cells but moxidectin was efficiently transported in BCRP-expressing X. laevis oocytes. The transport was blocked by an acridone derivative, a novel BCRP inhibitor. Moxidectin secretion into breast milk was decreased in Bcrp1-knockout mice and the milk to plasma ratio was 2-fold higher in wild-type mice after i.v. administration. Drug accumulation in intestinal content, bile, and intestine was higher in wild-type mice but the plasma concentration was not different. Moxidectin is identified as a BCRP substrate since its Bcrp1-mediated secretion into breast milk and the involvement of Bcrp1 in intestinal and bile secretion has been demonstrated. This interaction has pharmacokinetic and toxicological consequences. The most important toxicological consequences of the interaction between BCRP and moxidectin may be related with the presence of drug residues in milk.


Journal of Veterinary Pharmacology and Therapeutics | 2011

Involvement of breast cancer resistance protein (BCRP/ABCG2) in the secretion of danofloxacin into milk: interaction with ivermectin

Rebeca Real; Estefanía Egido; Miriam Perez; Lucía González-Lobato; Borja Barrera; Julio G. Prieto; Ana I. Alvarez; Gracia Merino

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.

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Alfred H. Schinkel

Netherlands Cancer Institute

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Juan Carlos Espín

Spanish National Research Council

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