PMID- 10636865
OWN - NLM
STAT- MEDLINE
DCOM- 20000224
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 275
IP  - 3
DP  - 2000 Jan 21
TI  - beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine
      transporter.
PG  - 1699-707
AB  - 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.
FAU - Ganapathy, M E
AU  - Ganapathy ME
AD  - Department of Medicine, Medical College of Georgia, Augusta, Georgia 30912, USA. 
      mganapat@mail.mcg.edu
FAU - Huang, W
AU  - Huang W
FAU - Rajan, D P
AU  - Rajan DP
FAU - Carter, A L
AU  - Carter AL
FAU - Sugawara, M
AU  - Sugawara M
FAU - Iseki, K
AU  - Iseki K
FAU - Leibach, F H
AU  - Leibach FH
FAU - Ganapathy, V
AU  - Ganapathy V
LA  - eng
GR  - GM 54412/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cephalosporins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Organic Cation Transport Proteins)
RN  - 0 (SLC22A5 protein, human)
RN  - 0 (Solute Carrier Family 22 Member 5)
RN  - 17298-37-2 (propionylcarnitine)
RN  - 280111G160 (Cefadroxil)
RN  - 6DH1W9VH8Q (Acetylcarnitine)
RN  - 807PW4VQE3 (Cefepime)
RN  - 9NEZ333N27 (Sodium)
RN  - LVZ1VC61HB (Cephaloridine)
RN  - N762921K75 (Nitrogen)
RN  - S7UI8SM58A (Carnitine)
SB  - IM
MH  - Acetylcarnitine/pharmacokinetics
MH  - Animals
MH  - Anti-Bacterial Agents/*metabolism
MH  - Carnitine/analogs & derivatives/antagonists & inhibitors/*pharmacokinetics
MH  - Carrier Proteins/*metabolism
MH  - Cefadroxil/pharmacology
MH  - Cefepime
MH  - Cephaloridine/pharmacokinetics
MH  - Cephalosporins/chemistry/pharmacokinetics
MH  - Dose-Response Relationship, Drug
MH  - HeLa Cells
MH  - Humans
MH  - Kinetics
MH  - Membrane Proteins/*metabolism
MH  - Nitrogen/metabolism
MH  - *Organic Cation Transport Proteins
MH  - Rats
MH  - Sodium/metabolism
MH  - Solute Carrier Family 22 Member 5
MH  - Tumor Cells, Cultured
EDAT- 2000/01/15 09:00
MHDA- 2000/02/26 09:00
CRDT- 2000/01/15 09:00
PHST- 2000/01/15 09:00 [pubmed]
PHST- 2000/02/26 09:00 [medline]
PHST- 2000/01/15 09:00 [entrez]
AID - 10.1074/jbc.275.3.1699 [doi]
AID - S0021-9258(18)31098-6 [pii]
PST - ppublish
SO  - J Biol Chem. 2000 Jan 21;275(3):1699-707. doi: 10.1074/jbc.275.3.1699.