Cited by 175Drug Transport and Resistance MechanismsAntibiotics Pharmacokinetics and EfficacyAmino Acid Enzymes and Metabolism

β-Lactam Antibiotics as Substrates for OCTN2, an Organic Cation/Carnitine Transporter

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Ganapathy, Malliga E., Huang, Wei, Rajan, D.Prasanna, Carter, A.Lee, Sugawara, Mitsuru, Iseki, Ken, Leibach, Frederick H., Ganapathy, Vadivel·2000·Journal of Biological Chemistry

Abstract

Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is associated with carnitine deficiency. A potential mechanism for the development of carnitine deficiency is competition between cephaloridine and carnitine for the renal reabsorptive process. OCTN2 is an organic cation/carnitine transporter that is responsible for Na(+)-coupled transport of carnitine in the kidney and other tissues. We investigated the interaction of several beta-lactam antibiotics with OCTN2 using human cell lines that express the transporter constitutively as well as using cloned human and rat OCTN2s expressed heterologously in human cell lines. The beta-lactam antibiotics cephaloridine, cefoselis, cefepime, and cefluprenam were found to inhibit OCTN2-mediated carnitine transport. These antibiotics possess a quaternary nitrogen as does carnitine. Several other beta-lactam antibiotics that do not possess this structural feature did not interact with OCTN2. The interaction of cephaloridine with OCTN2 is competitive with respect to carnitine. Interestingly, many of the beta-lactam antibiotics that were not recognized by OCTN2 were good substrates for the H(+)-coupled peptide transporters PEPT1 and PEPT2. In contrast, cephaloridine, cefoselis, cefepime, and cefluprenam, which were recognized by OCTN2, did not interact with PEPT1 and PEPT2. The interaction of cephaloridine with OCTN2 was Na(+)-dependent, whereas the interaction of cefoselis and cefepime with OCTN2 was largely Na(+)-independent. Furthermore, the Na(+)-dependent, OCTN2-mediated cellular uptake of cephaloridine could be demonstrated by direct uptake measurements. These studies show that OCTN2 plays a crucial role in the pharmacokinetics and therapeutic efficacy of certain beta-lactam antibiotics such as cephaloridine and that cephaloridine-induced carnitine deficiency is likely to be due to inhibition of carnitine reabsorption in the kidney.

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Crossref · 10.1074/jbc.275.3.1699

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  • Organic cation/carnitine transporter-2 (OCTN2) transports carnitine, an essential cofactor for fatty acid oxidation in mitochondria.

    “Organic cation/carnitine transporter-2 (OCTN2) transports carnitine, an essential cofactor for fatty acid oxidation in mitochondria (192).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [192]

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Authors
Ganapathy, M. E., Huang, W., Rajan, D. P., Carter, A. L., Sugawara, M., Iseki, K., Leibach, F. H., & Ganapathy, V.
Affiliations
  • Augusta University (US)
  • Hokkaido University Hospital (JP)
Corresponding author
Ganapathy, Malliga E.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2000-01
Volume
275
Issue
3
Pages
1699-1707
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1966267502
Cited by
175
References
31
Citations by year
2026: 1 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 2 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 8 · 2014: 3 · 2013: 7 · 2012: 9
FWCI
3.09
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01gm054412-03)
  • National Institute of General Medical Sciences (GM54412)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Pharmacology › Antibiotics Pharmacokinetics and Efficacy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
OCTN2, beta-lactam antibiotics, cephaloridine, carnitine deficiency, competitive inhibition, PepT1, PEPT2, cefepime, pharmacokinetics, drug-transporter interactions
MeSH terms
Solute Carrier Family 22 Member 5, Cefepime, Acetylcarnitine, Animals, Anti-Bacterial Agents, Carnitine, Carrier Proteins, Cefadroxil, Cephaloridine, Cephalosporins, Dose-Response Relationship, Drug, HeLa Cells, Humans, Kinetics, Membrane Proteins, Nitrogen, Sodium, Tumor Cells, Cultured, Organic Cation Transport Proteins, Rats

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