Interaction of Intestinal Nucleoside Transporter hCNT2 with Amino Acid Ester Prodrugs of Floxuridine and 2-Bromo-5,6-dichloro-1-.BETA.-D-ribofuranosylbenzimidazole

Abstract

Targeting a specific molecule toward transporters by designing its prodrugs may be used to improve oral bioavailability or to reduce systemic toxicity. [1][2][3][4][5][6] Valine prodrugs of acyclovir and ganciclovir, valacyclovir and valganciclovir, respectively, exhibit 3-5 times higher systemic exposure than the parent compounds. [7][8][9] Enhanced bioavailabilities of the amino acid prodrugs is attributed to carrier mediated intestinal absorption via intestinal transporters such as a human peptide transporter hPept1 or an amino acid transporter ATB 0,ϩ . 4,[10][11][12] Nucleoside antiviral and anticancer agents are important class of drugs for the fight against viral diseases and cancer. However, they often exhibit poor pharmaceutical and absorption, distribution, metabolism and excretion (ADME) properties. Prodrug approaches that can potentially improve their pharmaceutical and ADME properties can be of great benefit in realizing the full potential of these agents.Clinically important nucleoside drugs such as cladribine, dideoxyinosine, fludarabine, acyclovir, ganciclovir, and abacavir, gemcitabine, azidothymidine, FUdR, cytarabine, zalcitabine and stavudine are known to interact with nucleoside transporters, which can influence their ADME properties. [13][14][15] A sodium-dependent concentrative nucleoside transporter hCNT2 has been cloned from human intestine. [16][17][18] The hCNT2 is abundantly expressed in the intestinal tissues, and is involved in transport of both naturally occurring nucleosides and clinically relevant nucleoside analogs. 13,18) Of the subtypes of concentrative nucleoside transporter hCNT1-3, hCNT2 exhibits a preference for purine nucleosides over pyrimidine nucleosides. 13,19) FUdR is a fluorinated pyrimidine nucleoside drug extensively used in the treatment of colon cancer. Although the mechanism of action and therapeutic effectiveness of FUdR are well understood, it has various side effects in gastrointestinal and bone marrow tissues. 20) Hence, FUdR is administered parenterally due to its poor oral bioavailability. Recently, benzimidazole nucleosides such as BDCRB, maribavir, and GW275175X have also been developed as a new class of antiviral drugs. [21][22][23] Although BDCRB was found to be a potent and selective inhibitor of human cytomegavirus (HCMV) replication, it had a poor pharmacokinetics profile with a very short plasma half-life and cytotoxicity. 24,25) In this regard, we attempted to develop amino acid ester prodrugs of FUdR and BDCRB to improve their pharmacokinetic properties. Although considerable progress has been made in the development of amino acid or dipeptide nucleoside prodrugs, little is known about the nucleoside transporters involved in the intestinal absorption of the prodrugs. In a previous report, 18) we demonstrated that FUdR and BDCRB were potent inhibitors of intestinal nucleoside transporter hCNT2. This suggests that hCNT2 may play an important role in the uptake of nucleoside compounds from the intestine. Therefore, it is relevant to characterize ho...

Identification and Characterization of Proximal Promoter Polymorphisms in the Human Concentrative Nucleoside Transporter 2 (SLC28A2)

“…Human CNT2 is localized to the apical membranes of absorptive epithelial cells of the intestine, kidney, and liver and is also expressed in lymphocytes (Gray et al, 2004;Ferná ndez-Veledo et al, 2006;Meier et al, 2007;Minuesa et al, 2008). The role of CNT2 in the disposition and response to anticancer and antiviral nucleoside drugs has been characterized in intestinal tissues (Shin et al, 2006), renal epithelium (Damaraju et al, 2007;Elwi et al, 2009), and lymphocytes (Molina-Arcas et al, 2003;Minuesa et al, 2008). In addition, the expression of the CNT2 in hepatocytes and macrophages has led to an understanding of the endogenous physiological role of CNT2 in the salvage of nucleosides during cell proliferation .…”

Gordon L. Amidon: Very Sustained Drug Absorption

“…During the 2000s, he synthesized many amino acid and peptide prodrugs for investigating carrier‐mediated transport. Many of the prodrugs were amino acid prodrugs of nucleoside analogues as they were already understood to be carrier‐mediated . Carrier‐mediated transport by the peptide carrier (hPEPT1) seemed to have less specificity than most carriers and thus is quite amenable to prodrug variation.…”

Recent Trends in Targeted Anticancer Prodrug and Conjugate Design

“…Upon absorption, valacyclovir is rapidly converted to its parent drug acyclovir via esterase cleavage. Acyclovir is then free to enter the blood stream, where it can be taken up by cells via nucleoside transporters [113,121,127].…”

“…Floxuridin (FUDR) like many of its nucleoside counterparts (acyclovir included) is plagued by low and variable bioavailability, as well as adverse reactions, despite its well-characterized clinical effectiveness [127,133]. Various classical prodrug design methods have been employed, including linking FUDR to aliphatic carboxylic acid chains to improve drug permeability [134].…”