Interaction between pivaloylcarnitine and L-carnitine transport into L6 cells overexpressing hOCTN2.

Patients ingesting pivalic acid containing prodrugs develop hypocarnitinemia. Pivalic acid is cleaved from such drugs and excreted renally as pivaloylcarnitine. Plasma concentrations (reflecting the concentration in the glomerular filtrate entering the proximal tubule) in patients treated with cefditoren pivoxil are approximately 5 microM for pivaloylcarnitine and 10 microM for carnitine. Kinetic studies were performed using L6 cells overexpressing the human kidney carnitine transporter (hOCTN2) to assess the mechanisms leading to hypocarnitinemia in such patients. L-carnitine transport showed saturation kinetics (K(m) 6.3 microM) and could be inhibited competitively by pivaloylcarnitine (K(i) 70 microM). Pivaloylcarnitine was also transported by OCTN2 (K(m) 212 microM) and its transport could be inhibited competitively by L-carnitine (K(i) 7.8 microM). Haldane and Eadie-Hofstee plots were linear for both carnitine and pivaloylcarnitine. Our data indicate that both carnitine and pivaloylcarnitine bind to OCTN2 at a single, identical site. Considering the low plasma and tubular pivaloylcarnitine concentration, the high K(m) of pivaloylcarnitine regarding OCTN2 and the inhibition of pivaloylcarnitine transport by carnitine, pivaloylcarnitine is unlikely to be reabsorbed under these conditions. On the other hand, our data indicate that the renal reabsorption of carnitine is not impaired in patients treated with pivalic acid containing prodrugs. Hypocarnitinemia in such patients therefore develops due to massive renal losses of pivaloylcarnitine and not due to inhibition of carnitine reabsorption by pivaloylcarnitine.