Tissue selective drug delivery utilizing carrier-mediated transport systems

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Abstract

This paper describes some successful examples of a tissue selective drug delivery by utilizing specialized transporter(s) expressed in the targeted tissue cells. These are as follows: (1) oral delivery via H+/oligopeptide transporter, rat or human Pept1, in the intestine for β-lactam antibiotics and a newly synthesized dipeptide, l-dopa–l-phenylalanine; (2) tumor cell specific delivery via the newly discovered H+/oligopeptide transporter(s) expressed in human fibrosarcoma cell line HT-1080 for model oligopeptides, glycylsarcosine and carnosine; (3) oral and hepatic delivery via an H+/monocarboxylate transporter in the intestine and an organic anion transporter in the liver for HMG-CoA reductase inhibitor, pravastatin; and (4) lung selective delivery via some type of transporter and avoidance of transfer into the brain via P-glycoprotein at the blood–brain barrier for a new quinolone antibacterial, HSR-903.

Introduction

In order for a drug candidate to exhibit the expected pharmacological effect in vivo, the molecule must circumvent various biological barriers, including epithelial (e.g., intestinal, nasal, pulmonary) and endothelial barriers [e.g., endothelial cells that constitute the blood–brain barrier (BBB)]. Since lipophilicity and molecular size have long been believed to be determinant of the membrane transport of synthesized drugs in various tissue cells, for oral delivery of the candidate drug, pharmaceutical scientists have tended to put a highly lipophilic nature into the drug molecule. However, this strategy has often resulted in a poor oral bioavailability due to poor dissolution rate in the GI lumen, extensive first-pass metabolism in the intestine and/or liver, secretion from the intestinal epithelial cells and into bile across the bile canalicular membrane by several multidrug transporters such as P-glycoprotein (P-gp) and cMOAT, or in the easy penetration from the circulation into the brain to cause severe side effects in the central nervous system (CNS).

Direct and indirect evidence has been accumulated, by the recent cellular and molecular studies on the membrane transports of drugs, for participation of carrier-mediated membrane transports of several drugs in various tissues [1], [2], [3]. Therefore, utilization of transporters expressed in the target tissues seems to be an attractive strategy, by a chemical modification of drugs, to regulate the absorption from the intestine, the transfer into or the efflux from the brain across the BBB, and the excretion from the liver and kidney.

The objectives of the present study were to describe some successful examples of the intestinal and tumor selective delivery via H+/oligopeptide transporters for peptide-mimetic drugs, intestine and liver selective delivery via an H+/monocarboxylate transporter and an organic anion transporter for HMG-CoA reductase inhibitor, pravastatin and lung selective delivery via a specialized transporter and avoidance of transfer into brain via P-gp at the BBB for new quinolone antibacterials.

Section snippets

Materials

[Glycine-1-14C]glycylsarcosine ([14C]glycylsarcosine, 60 mCi/mmol) and [14C]inulin (210 MBq/g) were obtained from Amersham (Buckinghamshire, UK) and DuPont (Wilmington, DE, USA), respectively. Pravastatine, [3H]pravastiatin and cephalosporins were gifts. HSR-903, (S)-(−)-5-amino-7-(7-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid methanesulfonate, [14C]HSR-903 (specific activity, 256 kBq/mg base) and other quinolone derivatives were

Intestinal absorption of peptide-mimetic drugs via H+/oligopeptide transporter, PepT1

Recently, a rabbit cDNA was isolated [10] that encodes a 707-amino acid peptide transporter, termed PepT1. A human homologue, hPepT1, that shares 81% amino acid sequence identity with rabbit PepT1 was isolated from the intestine [5]. We have also cloned the homologue of rabbit PepT1 gene from a rat intestinal cDNA library [4]. The rat PepT1 is composed of 710 amino acids and the predicted amino acid sequence shows 77 and 83% identity with rabbit and human PepT1, respectively [4], [5], [6].

Conclusion

Recent advance in membrane transport studies with the use of molecular biological approaches have confirmed the participation of carrier-mediated transports in various tissues and the pharmacological and/or pharmacokinetical relevance of these transporters to the disposition of xenobiotics. Furthermore, the tissue distributions of these transporters suggest the physiological significance of carrier-mediated transport of nutrients, endogenous substrates and xenobiotics in many tissues, in

Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan and a grant from the Japan Foundation, Drug Innovation Project.

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