Abstract
L-carnitine is required for many physiological roles as participating in β-oxidation. Human OCTN2 (organic cation/carnitine transporter 2; SLC22A5), and its rat ortholog Octn2 (rSlc22a5), are ubiquitously-expressed membrane proteins that are hypothesized to be sodium-dependent specific transporters of L-carnitine. Although not generally regarded as a drug transporter, its role in drug pharmacokinetics has been clearly shown, particularly in relation to renal excretion.
Mildronate, is a carnitine congener which acts to inhibit fatty acid oxidation and has been shown to be transported by rat Octn2. However, characterization of kinetics of transport has not been described.
Aims: To correlate transport properties of Octn2 and OCTN2 and investigate mildronate transport by Octn2/OCTN2 in particular. Identify and examine drugs inhibiting L-carnitine uptake, and to perform a species specificity analysis of the rat and human orthologs.
Methods and results: Cellular uptake assays were performed using CHO-K1 cell lines stably overexpressing OCTN2 or Octn2 to examine species differences between the two transporters. Uptake of L-carnitine was quantitated using radiolabelled compound, whereas the detection of mildronate was carried out using HPLC-MS. Among others amiloride, imatinib, mildronate, omeprazole, quinine, quinidine and vincristine were used to examine their influence on L-carnitine uptake.
Conclusion: ?Similarly to OCTN2, Octn2 also transports mildronate with high potency. However, L-carnitine was found to be a lower affinity substrate for Octn2 than for OCTN2. Furthermore, many pharmacologically important drugs were shown to affect L-carnitine transport by Octn2/OCTN2, although several differences between rat and the human orthologs were also observed.
