Identification and Species Similarity of OATP Transporters Responsible for Hepatic Uptake of β-Lactam Antibiotics

Nakakariya, Masanori; Shimada, Toru; Irokawa, Masanori; Maeda, Tomoji; Tamai, Ikumi

doi:10.2133/dmpk.23.347

Cited by 64 publications

(38 citation statements)

References 24 publications

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“…Other substrates (rifampicin and penicillin for OATP1B1; rifampicin, penicillin, cefmetazole, and cefoperazone for OATP1B3) were consistent with previous reports. 21,25,26) The report by Nakakariya et al, 26) which demonstrated that cefoperazone is transported by OATP1B1 and that cefazolin is transported by both OATP1B1 and OATP1B3, was inconsistent with our results. We did not perform the uptake study if the transporter-mediated uptake did not decrease to 50% of the control uptake at the maximum inhibitory concentration.…”

Section: Discussioncontrasting

confidence: 99%

Screening of Antibiotics That Interact with Organic Anion-Transporting Polypeptides 1B1 and 1B3 Using Fluorescent Probes

Yamaguchi

Takeuchi

Okada

et al. 2011

Biological & Pharmaceutical Bulletin

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Hepatic organic anion transporters OATP1B1 and OATP1B3 are expressed at the sinusoidal membrane of hepatocytes and contribute to the hepatic uptake of a wide variety of clinically used drugs. To identify the antibiotics that interact with the human organic anion transporters OATP1B1 and OATP1B3, we applied a screening system using fluorescent probes. Twenty-six antibiotics with a variety of mechanisms of action were examined. The screening demonstrated that four antibiotics inhibited OATP1B1-mediated transport and 11 antibiotics inhibited OATP1B3-mediated transport in a concentration-dependent manner. Antibiotics that inhibited OATP1B3-mediated transport tended to exhibit higher affinity than those that inhibited OATP1B1-mediated transport. To clarify whether the antibiotics that interacted with OATP1B1 and/or OATP1B3 were substrates for these transporters, an uptake study was performed. Rifampicin and penicillin were transported by both OATP1B1 and OATP1B3. Moreover, OATP1B3 was involved in the transport of ceftriaxone, cefmetazole, cefoperazone, and cefotaxime. Macrolides were not significantly transported by either transporter. In conclusion, the results demonstrated that our system is a useful method for the rapid screening of transporter-antibiotic interaction, and we found novel substrates. Our results indicate that OATP1B1 and/or OATP1B3 contribute to the transport process of some antibiotics, and that drug-drug interactions associated with these transporters could occur after the administration of antibiotics.

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Section: Discussioncontrasting

confidence: 99%

Screening of Antibiotics That Interact with Organic Anion-Transporting Polypeptides 1B1 and 1B3 Using Fluorescent Probes

Yamaguchi

Takeuchi

Okada

et al. 2011

Biological & Pharmaceutical Bulletin

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“…In such cases, there might be potential competition between Ba and non-steroidal antiinflammatory drugs (NSAIDS) such as acetaminophen, ibuprofen or naproxen, etc. on phase II metabolic enzymes (26) or potential competition between Ba conjugates and NSAIDS conjugates on MRPs (27,28), as well as potential competition between Ba conjugates and antibiotics such as beta-lactam antibiotics on OATPs (29). All of those interactions may lead to the alteration of the clinical pharmacokinetic profiles of Western drug and should be taken into consideration in designing a therapeutic regimen.…”

Section: −1mentioning

confidence: 99%

Hepatic Metabolism and Disposition of Baicalein via the Coupling of Conjugation Enzymes and Transporters—In Vitro and In Vivo Evidences

Zhang

Lin

et al. 2011

AAPS J

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Abstract. Baicalein (Ba) was found to be subject to serious first-pass metabolism after oral administration. We previously revealed the important role of intestine in the low oral bioavailability of Ba. The present study aims to evaluate the hepatic metabolism and disposition of Ba. Ba was given to Sprague-Dawley rats through bolus or infusion via intravenous or intra-portal route of administrations. Both plasma and bile samples at different time intervals were obtained. Concentrations of Ba and potential metabolites in the collected samples were analyzed with HPLC/UV and identified by LC/MS/ MS, respectively. Plasma concentration versus time profiles of Ba obtained from intravenous and intraportal administrations were compared to estimate the extent of hepatic metabolism. In addition, transport studies of baicalein-7-glucuronide (BG), one of the major metabolites of Ba, were carried out using transfected cell systems overexpressing various human organic anion-transporting polypeptide (OATP) isoforms to estimate the specific transporters involved in the hepatic disposition of Ba metabolites. The results showed that liver, in addition to intestine, also conferred extensive metabolism to Ba. Several mono-and di-conjugates of Ba, which were mainly glucuronides, sulfates, and methylates, were found in bile. The transport study demonstrated that besides MRPs and BCRP, human OATP2B1 and OATP1B3 in liver might also mediate the secretion of BG to bile. In summary, liver plays an important role in the metabolism of Ba and transport of its conjugated metabolites.

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“…22) In general, uptake reaction was initiated by placing the cells in transport buffer (136.7 mM NaCl, 5. Transport Study Using Xenopus laevis Oocytes Complementary RNAs (cRNAs) of human OAT2 were prepared using a mMESSAGE mMACHINE kit according to manufacturer's instruction (Ambion, Austin TX, U.S.A.).…”

Section: Chemicalsmentioning

confidence: 99%

Renal Secretion of Uric Acid by Organic Anion Transporter 2 (OAT2/SLC22A7) in Human

Sato

Mamada

Anzai

et al. 2010

Biological & Pharmaceutical Bulletin

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The physiological function of organic anion transporter OAT2 (SLC22A7) remains unclear, but since OAT2 transports purine derivatives, it may be involved in renal handling of uric acid, the final metabolite of purine derivatives. In the present study, we studied uric acid transport in stably OAT2-expressing HEK293 cells (HEK293/OAT2). OAT2 mediated uptake, but not efflux, of [ ]uric acid uptake was inhibited by several mono-or dicarboxylic acids, but it was not trans-stimulated by any of the compounds tested. The pattern of inhibition of OAT2-mediated uric acid transport by various drugs was different from that of OAT1-or OAT3-mediated transport. Furthermore, OAT2-mediated transport of uric acid was inhibited by an antiuricosuric drug, pyrazinecarboxylic acid. These results revealed distinct characteristics of uric acid transport via OAT2 compared with other uric acid transporters, suggesting that OAT2 plays a role in renal uric acid uptake from blood as a first step of tubular secretion. OAT2 may therefore be a potential target for regulating serum uric acid level.

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Identification and Species Similarity of OATP Transporters Responsible for Hepatic Uptake of β-Lactam Antibiotics

Cited by 64 publications

References 24 publications

Screening of Antibiotics That Interact with Organic Anion-Transporting Polypeptides 1B1 and 1B3 Using Fluorescent Probes

Screening of Antibiotics That Interact with Organic Anion-Transporting Polypeptides 1B1 and 1B3 Using Fluorescent Probes

Hepatic Metabolism and Disposition of Baicalein via the Coupling of Conjugation Enzymes and Transporters—In Vitro and In Vivo Evidences

Renal Secretion of Uric Acid by Organic Anion Transporter 2 (OAT2/SLC22A7) in Human

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