Combination of l-Carnitine with Lipophilic Linkage-Donating Gemcitabine Derivatives as Intestinal Novel Organic Cation Transporter 2-Targeting Oral Prodrugs.

Novel organic cation transporter 2 (OCTN2, SLC22A5) is responsible for the uptake of carnitine through the intestine and, therefore, might be a promising molecular target for designing oral prodrugs. Poor permeability and rapid metabolism have greatly restricted the oral absorption of gemcitabine. We here describe the design of intestinal OCTN2-targeting prodrugs of gemcitabine by covalent coupling of l-carnitine to its N4-amino group via different lipophilic linkages. Because of the high OCTN2 affinity, the hexane diacid-linked prodrug demonstrated significantly improved stability (3-fold), cellular permeability (15-fold), and oral bioavailability (5-fold), while causing no toxicity as compared to gemcitabine. In addition, OCTN2-targeting prodrugs can simultaneously improve the permeability, solubility, and metabolic stability of gemcitabine. In summary, we present the first evidence that OCTN2 can act as a new molecular target for oral prodrug delivery and, importantly, the linkage carbon chain length is a key factor in modifying the affinity of the substrate for OCTN2.