ReviewTransporter-mediated drug delivery: recent progress and experimental approaches
Section snippets
Typical transporter candidates for drug delivery
The SLC family consists of 43 gene subfamilies and a total of ~300 family members, including ion-coupled transporters, facilitated transporters and exchangers (http://www.bioparadigms.org/slc/). In the ABC transporter family, 56 genes have been identified and classified into seven subfamilies (http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html). Some of these transporters accept not only physiological or endogenous substrates, but also xenobiotics, including drugs, and are therefore
Liver-selective distribution of an HMG-CoA reductase inhibitor
Pravastatin, an HMG-CoA reductase inhibitor that undergoes enterohepatic circulation, which prolongs the exposure of the target organ – the liver – and minimizes adverse effects in other tissues. Hisang et al. first described a liver-specific transporter, OATP-C/OATP2/LST1 (SLC21A6) (Table 2) that accepts pravastatin as a substrate [2]. Nakai et al. confirmed that the active and Na+-independent pravastatin uptake in the liver is mostly mediated by OATP-C in human hepatocytes [3]. After exerting
Transporter-mediated oral drug absorption
The oral route is preferable for the treatment of chronic diseases. For the rational design of orally active drugs, it is important to understand the mechanisms underlying intestinal absorption. Many factors influence absorption of drugs, including gastric emptying, pH, food, dissolution, lipophilicity, particle size, passive or active membrane permeation and active exclusion.
Recently, transporter-mediated processes have attracted great interest. Certain organic solutes, such as amino
Tumor-targeted delivery of drugs using an oligopeptide transporter
An oligopeptide transport activity is expressed in some tumor cells, including fibrosarcoma HT-1080 and two pancreatic tumor cell lines – AsPc-1 and Capan-2 – but not in a normal diploid cell line, IMR-90 [55, 56]. These findings open up a means for specific delivery of drugs to the tumor cells, because oligopeptide transporters, namely PEPT1 and PEPT2, are expressed mainly in the small intestinal epithelial cells and the renal proximal cells among non-tumor cells. To pursue the possibility of
Brain delivery of drugs by heterologous expression of a transporter in the BBB
Toyobuku et al. [61] examined the feasibility of heterologous transduction of a transporter gene to the BBB. Peptides have multiple biological actions in the brain, therefore, they are potentially valuable as neuropharmaceuticals in the treatment of various disorders, such as Alzheimer's disease and depression. Delivery of peptide drugs to the brain, however, is a big challenge because distribution of peptides to the brain is generally very low owing to the BBB. Toyobuku et al. constructed a
Summary and perspectives
With the help of great progress in key pharmaceutical technologies, we are now entering a new era of drug delivery. A comprehensive list of drug transporters has become available and now information on the tissue distributions and the mechanisms of these transporters is accumulating. However, as the transport mechanisms for the majority of drugs still remain to be clarified, much work remains to be done. In general, most SLC transporters and ABC transporters mediate influx and efflux transport,
References (71)
Tissue selective drug delivery utilizing carrier-mediated transport systems
J. Control. Release
(1999)Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family
Biochem. Biophys. Res. Commun.
(2000)Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver
Gastroenterology
(2001)Localization of the peptide transporter PEPT2 in the lung: implications for pulmonary oligopeptide uptake
Am. J. Pathol.
(2001)Differential recognition of beta-lactam antibiotics by intestinal and renal peptide transporters, PEPT 1 and PEPT 2
J. Biol. Chem.
(1995)Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2
Biochem. Biophys. Res. Commun.
(1998)- et al.
Transporter-mediated permeation of drugs across the blood-brain barrier
J. Pharm. Sci.
(2000) P-Glycoprotein influences the brain concentrations of cetirizine (Zyrtec), a second-generation non-sedating antihistamine
J. Pharm. Sci.
(2003)Intestinal solute carriers: an overview of trends and strategies for improving oral drug absorption
Eur. J. Pharm. Sci.
(2004)The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability
Eur. J. Pharm. Sci.
(2004)