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.