Synthesis and in vitro characterization of drug conjugates of l-carnitine as potential prodrugs that target human Octn2

Article abstract of DOI:10.1002/jps.22557

The objective was to evaluate the potential of drug conjugates with l-carnitine as prodrugs that target organic cation/carnitine transporter (OCTN2). Twenty-two l-carnitine analogues were evaluated for human organic cation/carnitine transporter (hOCTN2) inhibition; the 3'-hydroxyl group was found to be the only functional group not contributing to l-carnitine interaction with hOCTN2 among the three functional groups on l-carnitine (i.e., 3'-hydroxyl, amine, and carboxylate). The 3'-hydroxyl group on l-carnitine was therefore chosen as the conjugate site. Three drug-l-carnitine conjugates (i.e., valproyl-l-carnitine, naproxen-l-carnitine, and ketoprofen-l-carnitine) were synthesized along with two ketoprofen analogues that incorporated a linker group (glycolic acid or glycine) between ketoprofen and l-carnitine (i.e., ketoprofen-glycolic acid-l-carnitine and ketoprofen-glycine-l-carnitine). These potential prodrugs were evaluated for their in vitro inhibition, transport, and metabolism properties. All three drug-l-carnitine conjugates and ketoprofen-glycine-l-carnitine were OCTN2 inhibitors, as well as substrates. For valproyl-l-carnitine, K_i = 155± 19μM, K_m = 132± 23μM, and normalized J_max = 0.467± 0.028; for naproxen-l-carnitine, K_i = 5.97± 0.81μM, K_m = 257± 57μM, and normalized J_max = 0.141± 0.012; for ketoprofen-l-carnitine, K_i = 82.2± 5.3μM, K_m = 77.0± 4.0μM, and normalized J_max = 0.412± 0.015; for ketoprofen-glycine-l-carnitine, K_i = 14.4± 1.4μM, K_m = 58.5± 8.7μM, and normalized J_max = 0.0789± 0.0037. Ketoprofen-glycolic acid-l-carnitine was unstable in metabolic buffers and chemical buffers. On the contrary, naproxen-l-carnitine, ketoprofen-l-carnitine, and ketoprofen-glycine-l-carnitine were stable in chemical and metabolic buffers. The results demonstrate the potential of drug-l-carnitine conjugates to serve as prodrugs that target OCTN2.