Role of Na+/L-carnitine transporter (OCTN2) in renal handling of pivaloylcarnitine and valproylcarnitine formed during pivalic acid-containing prodrugs and valproic acid treatment.

Pivalic acid and valproic acid decreases L-carnitine concentration in the body via urinary excretion of their acylcarnitines, pivaloylcarnitine (PC) and valproylcarnitine (VC). To obtain an information about the mechanism of the physiological response, we investigated the renal handling of these acylcarnitines by Na+/L-carnitine cotransporter, OCTN2 using the isolated perfused rat kidney, rat OCTN2 (rOCTN2) and human OCTN2 (hOCTN2) expressing cells. In the perfused rat kidney, PC and VC were strongly reabsorbed with an efficiency comparable to L-carnitine, and these reabsorption were inhibited by 1 mM L-carnitine, suggesting that the interaction of L-carnitine with PC and VC reabsorption would be responsible for renal handling of these acylcarnitines in rats. The rOCTN2-mediated uptake of PC was lower than that of L-carnitine, whereas rOCTN2-mediated uptake of VC was as high as that of L-carnitine, indicating that contribution of rOCTN2 in renal handling of PC and VC would be different. Furthermore, hOCTN2-mediated uptake of these acylcarnitines was markedly lower than that of L-carnitine. On the other hand, both PC and VC inhibited L-carnitine reabsorption in the perfused rat kidney and their concentration-dependent inhibition was also observed for rOCTN2 and hOCTN2. These results suggest that low renal reabsorption and interaction of hOCTN2 for these acylcarnitines might possibly affect the decrease of L-carnitine concentration in humans.