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.

Involvement of recognition and interaction of carnitine transporter in the decrease of L-carnitine concentration induced by pivalic acid and valproic acid.

Purpose: Prodrugs with pivalic acid and valproic acid decrease L-carnitine concentration in plasma and tissues by urinary excretion of acylcarnitine as pivaloylcarnitine (PC) and valproylcarnitine (VC), respectively. We investigated the role of the Na+/L-carnitine cotransporter in the porcine kidney epithelial cell line, LLC-PK1 for the decrease of L-carnitine concentration.

Methods: The uptake of L-[3H]carnitine, acetyl-L-[3H]carnitine (AC), L-[3H]PC and L-[3H]VC were investigated in LLC-PK1 cells seeded in a 6-well culture plate.

Separate assessment of intestinal and hepatic first-pass effects using a rat model with double cannulation of the portal and jugular veins.

To separately assess intestinal and hepatic first-pass effects with absorption ratio data, we have established an experimental model of rats double-cannulated into the portal and jugular veins. The model allows us to take blood samples simultaneously from conscious rats that have recovered from surgical damage. Double cannulation did not alter the physiological and hematological conditions.