Organic Cation Transporter/Solute Carrier Family 22a is Involved in Drug Transfer into Milk in Mice

Ito, Naoki; Ito, Kousei; Ikebuchi, Yuki; Kito, Tomoko; Miyata, Hiroshi; Toyoda, Yu; Takada, Tappei; Hisaka, Akihiro; Honma, Masashi; Oka, Akira; Kusuhara, Hiroyuki; Suzuki, Hiroshi

doi:10.1002/jps.24138

Cited by 27 publications

(21 citation statements)

References 31 publications

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“…The Abcg2 KO mice (Ichida et al, 2012) had been maintained in our laboratory as described previously. All the animals were housed in temperature- and humidity-controlled animal cages with a 12-h dark-light cycle, and free access to water and standard animal chow (MF, Oriental Yeast Company, Tokyo, Japan) as described previously (Ito et al, 2014; Takada et al, 2015). In the present study, all the in vivo experiments were conducted with 6–8-week-old male mice.…”

Section: Methodsmentioning

confidence: 99%

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

et al. 2016

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ATP-binding cassette transporter G2 (ABCG2) is a plasma membrane protein that regulates the pharmacokinetics of a variety of drugs and serum uric acid (SUA) levels in humans. Despite the pharmacological and physiological importance of this transporter, there is no clinically available drug that modulates ABCG2 function. Therefore, to identify such drugs, we investigated the effect of drugs that affect SUA levels on ABCG2 function. This strategy was based on the hypothesis that the changes of SUA levels might caused by interaction with ABCG2 since it is a physiologically important urate transporter. The results of the in vitro screening showed that 10 of 25 drugs investigated strongly inhibited the urate transport activity of ABCG2. Moreover, febuxostat was revealed to be the most promising candidate of all the potential ABCG2 inhibitors based on its potent inhibition at clinical concentrations; the half-maximal inhibitory concentration of febuxostat was lower than its maximum plasma unbound concentrations reported. Indeed, our in vivo study demonstrated that orally administered febuxostat inhibited the intestinal Abcg2 and, thereby, increased the intestinal absorption of an ABCG2 substrate sulfasalazine in wild-type mice, but not in Abcg2 knockout mice. These results suggest that febuxostat might inhibit human ABCG2 at a clinical dose. Furthermore, the results of this study lead to a proposed new application of febuxostat for enhancing the bioavailability of ABCG2 substrate drugs, named febuxostat-boosted therapy, and also imply the potential risk of adverse effects by drug-drug interactions that could occur between febuxostat and ABCG2 substrate drugs.

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Section: Methodsmentioning

confidence: 99%

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

et al. 2016

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“…Although the induced expression in the lactating mammary gland (Jonker et al, 2005) is not exclusive for this ABC transporter (Farke et al, 2008;Mani et al, 2009;Ito et al, 2014), a clear effect of ABCG2 in the veterinary medicine field related with drug secretion into milk has been reported by several groups (Real et al, 2011a;Mealey, 2013). Cohen-Zinder et al (2005) described a nonsynonymous SNP (A/C, rs43702337) encoding a substitution of a Tyr by a Ser at position 581 (Y581S) of bovine ABCG2.…”

Section: Short Communicationmentioning

confidence: 95%

Short communication: The gain-of-function Y581S polymorphism of the ABCG2 transporter increases secretion into milk of danofloxacin at the therapeutic dose for mastitis treatment

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Barrera

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et al. 2015

Journal of Dairy Science

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The ATP-binding cassette transporter ABCG2 restricts the exposure of certain drugs and natural compounds in different tissues and organs. Its expression in the mammary gland is induced during lactation and is responsible for the active secretion of many compounds into milk, including antimicrobial agents. This particular function of ABCG2 may affect drug efficacy against mastitis and the potential presence of drug residues in the milk. Previous in vitro and in vivo studies showed increased transport of several compounds, including fluoroquinolones, by the bovine ABCG2 Y581S polymorphism. Our main purpose was to study the potential effect of this bovine ABCG2 polymorphism on the secretion into milk of the antimicrobial danofloxacin administered at the therapeutic dose of 6mg/kg used for mastitis treatment. In addition, the effect of this polymorphism on the relative mRNA and protein levels of ABCG2 by quantitative real-time PCR and Western blot were studied. Danofloxacin 18% (6mg/kg) was administered to 6 Y/Y homozygous and 5 Y/S heterozygous cows. Danofloxacin levels in milk and milk-to-plasma concentration ratios were almost 1.5- and 2-fold higher, respectively, in Y/S cows compared with the Y/Y cows, showing a higher capacity of this variant to transport danofloxacin into milk. Furthermore, the higher activity of this polymorphism is not linked to higher ABCG2 mRNA or protein levels. These results demonstrate the relevant effect of the Y581S polymorphism of the bovine ABCG2 transporter in the secretion into milk of danofloxacin after administration of 6mg/kg, with potentially important consequences for mastitis treatment and for milk residue handling.

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“…The transport assay reactions were purified using ENVI-Carb SPE columns (Sigma-Aldrich) and then lyophilized overnight, as outlined by Ito et al (2014), and then analyzed by LC-MS/MS. Nucleotide sugars were separated using a Hypercarb column (150 mm 3 1 mm, 5 mm) at a flow rate of 50 mL min 21 with an 1100 series HPLC system (Agilent Technologies) and a 4000 QTRAP LC-MS/MS system (Sciex) equipped with a Turbo ion spray ion source.…”

Section: Nucleotide Sugar Quantification Using Tandem Mass Spectrometrymentioning

confidence: 99%

UUAT1 Is a Golgi-Localized UDP-Uronic Acid Transporter That Modulates the Polysaccharide Composition of Arabidopsis Seed Mucilage

et al. 2017

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Organic Cation Transporter/Solute Carrier Family 22a is Involved in Drug Transfer into Milk in Mice

Cited by 27 publications

References 31 publications

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

Identification of Febuxostat as a New Strong ABCG2 Inhibitor: Potential Applications and Risks in Clinical Situations

Short communication: The gain-of-function Y581S polymorphism of the ABCG2 transporter increases secretion into milk of danofloxacin at the therapeutic dose for mastitis treatment

UUAT1 Is a Golgi-Localized UDP-Uronic Acid Transporter That Modulates the Polysaccharide Composition of Arabidopsis Seed Mucilage

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