Intestinal OCTN2- and MCT1-targeted Drug Delivery to Improve Oral Bioavailability

Overview

Journal Asian J Pharm Sci

Date 2020 Apr 8

PMID 32256846

Citations 9

Authors

Gang Wang

Lichun Zhao

Qikun Jiang

Yixin Sun

Dongyang Zhao

Mengchi Sun

Zhonggui He

Jin Sun

Yang Wang

Affiliations

Soon will be listed here.

Abstract

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs, thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery. In particular, intestinal carnitine/organic cation transporter 2 (OCTN2) and mono-carboxylate transporter protein 1 (MCT1) possess high transport capacities and complementary distributions. Therefore, we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review. First, basic information of the two transporters is reviewed, including their topological structures, characteristics and functions, expression and key features of their substrates. Furthermore, progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed, including improvements in the oral absorption of anti-inflammatory drugs, antiepileptic drugs and anticancer drugs. Finally, the potential of a dual transporter-targeting strategy is discussed.

Citing Articles

Comprehensive review of the expanding roles of the carnitine pool in metabolic physiology: beyond fatty acid oxidation.

Xiang F, Zhang Z, Xie J, Xiong S, Yang C, Liao D J Transl Med. 2025; 23(1):324.

PMID: 40087749 DOI: 10.1186/s12967-025-06341-5.

FOCUS on NOD2: Advancing IBD Drug Discovery with a User-Informed Machine Learning Framework.

Choudhary R, Mahadevan R ACS Med Chem Lett. 2024; 15(7):1057-1070.

PMID: 39015268 PMC: 11247655. DOI: 10.1021/acsmedchemlett.4c00148.

Recent advances in zwitterionic nanoscale drug delivery systems to overcome biological barriers.

Ouyang X, Liu Y, Zheng K, Pang Z, Peng S Asian J Pharm Sci. 2024; 19(1):100883.

PMID: 38357524 PMC: 10861844. DOI: 10.1016/j.ajps.2023.100883.

Design of chimeric GLP-1A using oligomeric bile acids to utilize transporter-mediated endocytosis for oral delivery.

Kweon S, Lee J, Yang S, Park S, Subedi L, Shim J Biomater Res. 2023; 27(1):83.

PMID: 37660070 PMC: 10474648. DOI: 10.1186/s40824-023-00421-7.

Transporter-Mediated Drug Delivery.

Gyimesi G, Hediger M Molecules. 2023; 28(3).

PMID: 36770817 PMC: 9919865. DOI: 10.3390/molecules28031151.

References

Srinivas S, Prasad P, Umapathy N, Ganapathy V, Shekhawat P . Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+). Am J Physiol Gastrointest Liver Physiol. 2007; 293(5):G1046-53. PMC: 3583010. DOI: 10.1152/ajpgi.00233.2007. View

Kinoshita M, Suzuki Y, Saito Y . Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation. Biochem Biophys Res Commun. 2002; 293(2):827-31. DOI: 10.1016/S0006-291X(02)00294-2. View

Halestrap A . The monocarboxylate transporter family--Structure and functional characterization. IUBMB Life. 2011; 64(1):1-9. DOI: 10.1002/iub.573. View

Ohashi R, Tamai I, Inano A, Katsura M, Sai Y, Nezu J . Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein. J Pharmacol Exp Ther. 2002; 302(3):1286-94. DOI: 10.1124/jpet.102.036004. View

Kirat D, Inoue H, Iwano H, Hirayama K, Yokota H, Taniyama H . Monocarboxylate transporter 1 gene expression in the ovine gastrointestinal tract. Vet J. 2006; 171(3):462-7. DOI: 10.1016/j.tvjl.2004.12.009. View

Cavaglieri C, Nishiyama A, Fernandes L, Curi R, Miles E, Calder P . Differential effects of short-chain fatty acids on proliferation and production of pro- and anti-inflammatory cytokines by cultured lymphocytes. Life Sci. 2003; 73(13):1683-90. DOI: 10.1016/s0024-3205(03)00490-9. View

Garcia C, Brown M, Pathak R, Goldstein J . cDNA cloning of MCT2, a second monocarboxylate transporter expressed in different cells than MCT1. J Biol Chem. 1995; 270(4):1843-9. DOI: 10.1074/jbc.270.4.1843. View

Sun Y, Sun J, Shi S, Jing Y, Yin S, Chen Y . Synthesis, transport and pharmacokinetics of 5'-amino acid ester prodrugs of 1-beta-D-arabinofuranosylcytosine. Mol Pharm. 2009; 6(1):315-25. DOI: 10.1021/mp800200a. View

Zhang E, Phelps M, Cheng C, Ekins S, Swaan P . Modeling of active transport systems. Adv Drug Deliv Rev. 2002; 54(3):329-54. DOI: 10.1016/s0169-409x(02)00007-8. View

10.

Lajoie J, Shusta E . Targeting receptor-mediated transport for delivery of biologics across the blood-brain barrier. Annu Rev Pharmacol Toxicol. 2014; 55:613-31. PMC: 5051266. DOI: 10.1146/annurev-pharmtox-010814-124852. View

11.

Wu X, Prasad P, Leibach F, Ganapathy V . cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun. 1998; 246(3):589-95. DOI: 10.1006/bbrc.1998.8669. View

12.

Okamura A, Emoto A, Koyabu N, Ohtani H, Sawada Y . Transport and uptake of nateglinide in Caco-2 cells and its inhibitory effect on human monocarboxylate transporter MCT1. Br J Pharmacol. 2002; 137(3):391-9. PMC: 1573497. DOI: 10.1038/sj.bjp.0704875. View

13.

Estudante M, Morais J, Soveral G, Benet L . Intestinal drug transporters: an overview. Adv Drug Deliv Rev. 2012; 65(10):1340-56. DOI: 10.1016/j.addr.2012.09.042. View

14.

Batrakova E, Zhang Y, Li Y, Li S, Vinogradov S, Persidsky Y . Effects of pluronic P85 on GLUT1 and MCT1 transporters in the blood-brain barrier. Pharm Res. 2004; 21(11):1993-2000. DOI: 10.1023/b:pham.0000048189.79606.6e. View

15.

Ohashi R, Tamai I, Yabuuchi H, Nezu J, Oku A, Sai Y . Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999; 291(2):778-84. View

16.

Welter H, Claus R . Expression of the monocarboxylate transporter 1 (MCT1) in cells of the porcine intestine. Cell Biol Int. 2008; 32(6):638-45. DOI: 10.1016/j.cellbi.2008.01.008. View

17.

Adema A, Smid K, Losekoot N, Honeywell R, Verheul H, Myhren F . Metabolism and accumulation of the lipophilic deoxynucleoside analogs elacytarabine and CP-4126. Invest New Drugs. 2011; 30(5):1908-16. PMC: 3432794. DOI: 10.1007/s10637-011-9756-8. View

18.

Schomig E, Spitzenberger F, Engelhardt M, Martel F, Ording N, Grundemann D . Molecular cloning and characterization of two novel transport proteins from rat kidney. FEBS Lett. 1998; 425(1):79-86. DOI: 10.1016/s0014-5793(98)00203-8. View

19.

Shimoyama Y, Kirat D, Akihara Y, Kawasako K, Komine M, Hirayama K . Expression of monocarboxylate transporter 1 (MCT1) in the dog intestine. J Vet Med Sci. 2007; 69(6):599-604. DOI: 10.1292/jvms.69.599. View

20.

Meier Y, Eloranta J, Darimont J, Ismair M, Hiller C, Fried M . Regional distribution of solute carrier mRNA expression along the human intestinal tract. Drug Metab Dispos. 2007; 35(4):590-4. DOI: 10.1124/dmd.106.013342. View