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Predominant Contribution of Rat Organic Anion Transporting Polypeptide-2 (Oatp2) to Hepatic Uptake of β-Lactam Antibiotics

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Abstract

Purpose

To identify the rat hepatic basolateral transporters involved in the hepatic uptake of β-lactam antibiotics using nafcillin as a model β-lactam antibiotic that undergoes extensive biliary excretion.

Materials and Methods

Uptake by isolated rat hepatocytes and Xenopus laevis oocytes expressing organic anion transporting peptides (Oatp1, 2, and 4) and organic anion transporter (OAT2) was evaluated.

Results

Nafcillin uptake by isolated rat hepatocytes was saturable with the K m of 210 μM and was significantly inhibited by anionic compounds (estrone-3-sulfate and sulfobromophthalein), but not by cationic compounds (tetraethylammonium and 1-methyl-4-phenylpyridinium). In an in vitro uptake study by Xenopus oocytes expressing hepatic basolateral membrane transporters, nafcillin was transported by multiple Oatps with K m values of 4120 μM (Oatp1/Oatp1a1), 198 μM (Oatp2/Oatp1a4), and 1,570 μM (Oatp4/Oatp1b2), though it was not transported by hOAT2. Comparison of affinity and analysis by the relative activity factor method indicated that Oatp2 is the predominant contributor to the hepatic uptake of nafcillin. Cefadroxil, cefazolin, cefmetazole, cefoperazone, cefsulodin, and cephalexin, though not cefotaxime or ceftriaxone, were also substrates of Oatp2.

Conclusion

These findings suggest that Oatp2 plays a key role in the hepatic uptake of nafcillin and most other β-lactam antibiotics in rats.

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Abbreviations

BSP:

sulfobromophthalein

E13S:

estrone-3-sulfate

MPP+ :

1-methyl-4-phenylpyridinium

Mrp:

multidrug resistance-associated protein

Ntcp:

Na+-taurocholate cotransporting polypeptide

OAT/Oat:

organic anion transporter

OATP/Oatp:

organic anion transporting polypeptide

PCG:

benzylpenicillin

RAF:

relative activity factor

TEA:

tetraethylammonium

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Acknowledgement

A part of this study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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Authors and Affiliations

  1. Department of Membrane Transport and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba, 278-8510, Japan

    Masanori Nakakariya, Taiki Shimada, Masanori Irokawa, Hiroyuki Koibuchi, Takashi Iwanaga, Tomoji Maeda & Ikumi Tamai

  2. GenoMembrane, Inc., Tsurumi-ku, Yokohama 230-0040, Kanagawa, Japan

    Hikaru Yabuuchi

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  1. Masanori Nakakariya
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Correspondence to Ikumi Tamai.

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Nakakariya, M., Shimada, T., Irokawa, M. et al. Predominant Contribution of Rat Organic Anion Transporting Polypeptide-2 (Oatp2) to Hepatic Uptake of β-Lactam Antibiotics. Pharm Res 25, 578–585 (2008). https://doi.org/10.1007/s11095-007-9427-9

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  • DOI: https://doi.org/10.1007/s11095-007-9427-9

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