beta-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter

Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is as sociated with carnitine deficiency. A potential mechanism for the developme nt of carnitine deficiency is competition between cephaloridine and carniti ne 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 be ta-lactam antibiotics with OCTN2 using human cell lines that express the tr ansporter constitutively as well as using cloned human and rat OCTN2s expre ssed heterologously in human cell lines. The beta-lactam antibiotics cephal oridine, cefoselis, cefepime, and cefluprenam were found to inhibit OCTN2-m ediated carnitine transport, These antibiotics possess a quaternary nitroge n as does carnitine, Several other beta-lactam antibiotics that do not poss ess this structural feature did not interact with OCTN2, The interaction of cephaloridine with OCTN2 is competitive with respect to carnitine, Interes tingly, many of the beta-lactam antibiotics that were not recognized by OCT N2 were good substrates for the H+-coupled peptide transporters PEPT1 and P EPT2, In contrast, cephaloridine, cefoselis, cefepime, and cefluprenam, whi ch were recognized by OCTN2, did not interact with PEPT1 and PEPT2, The int eraction of cephaloridine with OCTN2 was Na+-dependent, whereas the interac tion of cefoselis and cefepime with OCTN2 was largely Na+-independent, Furt hermore, the Na+-dependent, OCTN2-mediated cellular uptake of cephaloridine could be demonstrated by direct uptake measurements, These studies show th at OCTN2 plays a crucial role in the pharmacokinetics and therapeutic effic acy of certain beta-lactam antibiotics such as cephaloridine and that cepha loridine-induced carnitine deficiency is likely to be due to inhibition of carnitine reabsorption in the kidney.