title: Synthesis and in vitro characterization of drug conjugates of l-carnitine as potential prodrugs that target human Octn2.
abstract: 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 ± 19 μM, K(m)=132 ± 23 μM, and normalized J(max)=0.467 ± 0.028; for naproxen-l-carnitine, K(i)=5.97 ± 0.81 μM, K(m)=257 ± 57 μM, and normalized J(max)=0.141 ± 0.012; for ketoprofen-l-carnitine, K(i)=82.2 ± 5.3 μM, K(m)=77.0 ± 4.0 μM, and normalized J(max)=0.412 ± 0.015; for ketoprofen-glycine-l-carnitine, K(i)=14.4 ± 1.4 μM, K(m)=58.5 ± 8.7 μM, 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.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
authors: Lei
authors: L
authors: Diao
authors: James E
authors: JE
authors: Polli
mesh_terms: D000818:Animals; D002331:Carnitine / Q000138:chemical synthesis* / Q000494:pharmacology*; D002478:Cells, Cultured; D004285:Dogs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D027701:Organic Cation Transport Proteins / Q000187:drug effects*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D000074058:Solute Carrier Family 22 Member 5
chemical_list: D027701:Organic Cation Transport Proteins; D011355:Prodrugs; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D002331:Carnitine