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

https://doi.org/10.2133/dmpk.23.347Get rights and content

Summary:

The present study was designed to identify the organic anion transporting polypeptide (OATP) molecule(s) responsible for the uptake of β-lactam antibiotics in human liver, using cryopreserved hepatocytes, as well as Xenopus oocytes and cultured cells expressing human OATPs. Nafcillin uptake by human hepatocytes was saturable with a Km of 533 μM. In vitro uptake studies revealed that OATP1B3 and OATP1B1 transported nafcillin with Km values of 74 μM and 11 mM, respectively. Analysis by the relative activity factor method suggested that OATP1B3 contributes mainly to nafcillin uptake and OATP1B1 contributes moderately. This conclusion was supported by the results of a study with selective inhibitors. Furthermore, OATP1B3 transported six other β-lactam antibiotics, and their uptake clearances by OATP1B3 correlated well with those mediated by rat Oatp1a4, which is the predominant contributor to basolateral uptake of nafcillin by rat hepatocytes. These findings suggest that OATP1B3 plays a major role in the hepatic uptake of β-lactam antibiotics in humans, and probably corresponds functionally to Oatp1a4 in rat liver.

References (28)

  • D. Grundemann et al.

    Drug excretion mediated by a new prototype of polyspecific transporter

    Nature

    (1994)
  • T. Nozawa et al.

    Involvement of organic anion transporting polypeptide in the transport of troglitazone sulfate: Implications for understanding troglitazone hepatotoxicity

    Drug. Metab. Dispos.

    (2004)
  • T. Nozawa et al.

    Role of organic anion transporter OATP-C in hepatic uptake of irinotecan and its active metabolite SN-38: In vitro evidence and effect of single nucleotide polymorphisms

    Drug. Metab. Dispos.

    (2005)
  • T. Nozawa et al.

    Contribution of organic anion transporting polypeptide OATP-C (SLC21A6) to hepatic elimination of opioidpeptide [D-Ala2, D-Leu2]enkephalin

    J. Pharm. Pharmacol.

    (2003)
  • Cited by (57)

    • Predicting disruptions to drug pharmacokinetics and the risk of adverse drug reactions in non-alcoholic steatohepatitis patients

      2023, Acta Pharmaceutica Sinica B
      Citation Excerpt :

      Based on these data, the dysfunction in metabolizing enzyme and transporter activities can impact the pharmacokinetics of other drugs eliminated through the same pathways and can be involved in the onset of ADRs. According to this hypothesis, we aimed to identify a list of sensitive drugs whose ADME kinetics could be disrupted (Table 337,48,80,96,101–103,114,134–136,152,154,288,292-586). We applied the same methodology as for Tables 1 and 2 to perform bibliographic research to identify the drugs that have been described as substrates for transporters or metabolizing enzymes modified in NASH.

    • Interaction of swine organic anion transporting polypeptide 1a2 with tetracycline, macrolide and β-lactam antibiotics

      2019, Toxicology and Applied Pharmacology
      Citation Excerpt :

      Results of our current study seemed to suggest that sOatp1a2, which is dominantly expressed at the pig liver, may behave more similarly to human OATPs found in the hepatocytes. All three β-lactam antibiotics were found to be both inhibitors and substrates of sOatp1a2, a phenomenon that is similar to that observed in the human liver-specific transporter OATP1B3 (Nakakariya et al., 2008a) and the rat Oatp1a4, which was shown to be the predominant contributor to basolateral uptake of nafcillin by rat hepatocytes (Nakakariya et al., 2008b). All the tested β-lactam antibiotics exhibited similar IC50, though penicillin seemed to be a more potent substrate of sOatp1a2.

    • Evaluation of New Chemical Entities as Substrates of Liver Transporters in the Pharmaceutical Industry: Response to Regulatory Requirements and Future Steps

      2017, Journal of Pharmaceutical Sciences
      Citation Excerpt :

      By using Xenopus oocytes–expressing OATPs, they demonstrated that all the 7 β-lactam antibiotics tested in the study were transported by both OATP1B3 and Oatp1a4; in addition, 4 were transported by OATP1B1 as well. A good correlation was observed between the ranked order of transporter activity of OATP1B3 and that of OATP1a4.18 Based on these reports, rat is deemed a useful animal species for the qualitative evaluation of NCEs.

    • The effects of dietary and herbal phytochemicals on drug transporters

      2017, Advanced Drug Delivery Reviews
      Citation Excerpt :

      Thus, EGCG might inhibit hepatic uptake of an OCT1 substrate (e.g., metformin, sumatriptan) and increase its plasma concentration in patients drinking green tea or taking herbal supplements containing a high dose of EGCG. OATP1B1 (LST1/OATPC/OATP-2/SLCO1B3) is a liver-specific transporter that mediates the uptake into the hepatocytes of a broad range of drugs, including statins (e.g., pravastatin [191], fluvastatin [192]), antibiotics (e.g., rifampicin [193], beta lactam antibiotics [194]), angiotension II receptor blockers (e.g., olmesartan [195], valsartan [196]), HIV protease inhibitors [197], fexofenadine [198], methotrexate [199] and SN-38 [200], as well as several endogenous substrates, such as bile salts, conjugated steroids, eicosanoids, thyroid hormones and coproporphyrins I and III [201,28,165,202–204]. Accumulating evidence suggests that genetic variants affecting OATP1B1 activity are important determinants of the hepatic clearance of its substrates [205–207].

    View all citing articles on Scopus
    View full text