Limited Brain Distribution of [3R,4R,5S]-4-Acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate Phosphate (Ro 64-0802), a Pharmacologically Active Form of Oseltamivir, by Active Efflux across the Blood-Brain Barrier Mediated by Organic Anion Transporter 3 (Oat3/Slc22a8) and Multidrug Resistance-Associated Protein 4 (Mrp4/Abcc4)

Ose, Atsushi; Ito, Mototsugu; Kusuhara, Hiroyuki; Yamatsugu, Kenzo; Kanai, Motomu; Shibasaki, Masakatsu; Hosokawa, Masakiyo; Schuetz, John D.; Sugiyama, Yuichi

doi:10.1124/dmd.108.024018

Cited by 117 publications

(81 citation statements)

References 42 publications

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“…For example, the preferential substrates for CES1A1, a human CES1 family isozyme, are thought to be compounds esterified by small alcohols, while those for CES2A1, a human CES2 family isozyme, are thought to be compounds esterified by relatively large alcohols. CES1A1, but not CES2A1, hydrolyzed the methyl ester of cocaine and the ethyl esters of temocapril, meperidine, imidapril and oseltamivir (Pindel et al, 1997;Takai et al, 1997;Mori et al, 1999;Satoh et al, 2002;Furihata et al, 2004a;Shi et al, 2006;Ose et al, 2009).…”

Section: Drug Metabolismmentioning

confidence: 99%

Carboxylesterases: Structure, Function and Polymorphism

Satoh¹,

Hosokawa²

2009

Biomolecules and Therapeutics

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-This review covers current developments in molecular-based studies of the structure and function of carboxylesterases. To allay the confusion of the classic classification of carboxylesterase isozymes, we have proposed a novel nomenclature and classification of mammalian carboxylesterases on the basis of molecular properties. In addition, mechanisms of regulation of gene expression of carboxylesterases by xenobiotics, and involvement of carboxylesterase in drug metabolism are also described.

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Section: Drug Metabolismmentioning

confidence: 99%

Carboxylesterases: Structure, Function and Polymorphism

Satoh¹,

Hosokawa²

2009

Biomolecules and Therapeutics

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“…CES1A1, but not CES2A1, hydrolyzed the methyl ester of cocaine and the ethyl esters of temocapril, meperidine, imidapril and oseltamivir. 20,38,80,[89][90][91] It was interesting that procainamide inhibited CES1-mediated imidapril hydrolysis. 92) Procainamide is also known as a choline-binding pocket-specific inhibitor 93) and has been reported to competitively inhibit human BuChE.…”

Section: Possible Role Of Ce Isozymes In Drug Metabolismmentioning

confidence: 99%

Carboxylesterases: structure, function and polymorphism in mammals

Satoh

Hosokawa

2010

J. Pestic. Sci.

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“…Disruption of Oatp1a4 and Oat3 genes did not affect the integrity of the BBB or cause any adaptive regulation of the known xenobiotic transporters in the brain, at least at the mRNA level (Ose et al, 2009(Ose et al, , 2010. However, the efflux of taurocholate, rosuvastatin, pitavastatin, and Ro 64-0802 from the brain after microinjection was significantly delayed in Oatp1a4(Ϫ/Ϫ) and Oat3(Ϫ/Ϫ) mice, respectively, compared with that in the corresponding wild-type mice (Ose et al, 2009(Ose et al, , 2010. This result is consistent with the proposed roles of Oatp1a4 and Oat3 at the BBB.…”

Section: Introductionmentioning

confidence: 99%

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

Miyajima

Kusuhara²,

Fujishima³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The present study investigated the efflux transport systems of organic anions across the blood-brain barrier (BBB) using dehydroepiandrosterone sulfate (DHEAS) as a probe. The elimination of DHEAS from the brain after microinjection into the cerebral cortex was characterized in wild-type mice and mice with deficiency of well characterized organic anion transporters, organic aniontransporting polypeptide 1a4 (Oatp1a4)/Slco1a4 and organic anion transporter 3 (Oat3)/Slc22a8, at the BBB. The saturable efflux of DHEAS from the brain was completely inhibited by probenecid, benzylpenicillin, and estrone-3-sulfate and moderately inhibited by taurocholate and p-aminohippurate (50-57%). Uptake of DHEAS and estrone-3-sulfate was greater in murine Oat3 cRNA-injected oocytes than that in water-injected oocytes. Efflux of these compounds from the brain was significantly delayed in Oat3(؊/؊) mice compared with that in wild-type mice, indicating that indeed Oat3 is functionally important in vivo. Furthermore, probenecid and taurocholate inhibited DHEAS efflux completely in Oat3(؊/؊) mice. Contrary to the past report in rats that suggested involvement of Oatp1a4, specific uptake of DHEAS and estrone-3-sulfate by murine Oatp1a4 was not detected in vitro, and efflux of both compounds from the brain was not altered in Oatp1a4(؊/؊) mice. There was no significant difference in the uptake of DHEAS by brain slices prepared from wild-type, Oatp1a4(؊/؊), and Oat3(؊/؊) mice. Taken together, these results suggest that Oat3 plays a significant role in the efflux of steroid conjugates across the BBB in mice and that the BBB also expresses other unknown organic anion transporters for the efflux of DHEAS. Transport mechanisms of organic anions at the BBB are far more diverse than they were assumed to be.

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Cited by 117 publications

References 42 publications

Carboxylesterases: Structure, Function and Polymorphism

Carboxylesterases: Structure, Function and Polymorphism

Carboxylesterases: structure, function and polymorphism in mammals

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

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