Proteins drug-transporting

Recent advances in genomic and proteomic research have exponentially increased the number of potential protein therapeutic molecules that may be used for unmet therapeutical needs. However, to fully understand the therapeutical potential of these substances, a parallel development should be made in protein delivery technologies. These new technologies presumably offer the ability to overcome biochemical and anatomical barriers to protein drug transport, without overcoming adverse events, to deliver the drug(s) at a favorable rate and duration, to protect... 

Transporters are membrane proteins that control the influx of essential nutrients and ions and the efflux of cellular waste, environmental toxins, and other xenobiotics. Approximately 6% of genes in the human genome encode transporters or transporter-related proteins. Drug-transporting proteins contribute to both therapeutic and adverse effects of drugs (Figure 2-1). 

Taken together ABC-transporters represent a large family of proteins affecting the pharmacokinetic parameters of various drugs. Here, P-gp is currently the best characterized member and it may also be one of the most important ABC-transporters with regard to drug transport. However, it becomes more and more apparent that ABC-transporter act in a coordinated... 

Chan LM, Lowes S, Hirst BH (2004) The ABCs of drug transport in intestine and liver efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 21 25—51... 

Mao Q and Unadkat JD. Role of the breast cancer resistance protein (ABCG2) in drug transport. AAPS J 2005 7 E118-33. 

Limtraknl, P. et al.. Modulation of the function of three ABC drug transporters, P-glycoprotein (ABCBl), mitoxantrone resistance protein (ABCG2) and multidrug resistance protein 1 (ABCCl) by tetrahydroenrenmin, a major metabolite of cur-enmin. Mol. Cell Biochem., 296, 85, 2007. 

JD Verhoff, HE Bodde, AG deBoer, JA Bouwstra, HE Junginger, FWHM Merkus DD Breimer. Transport of peptide and protein drugs across biological membranes. Eur J Drug Metab Pharmacokin 15 83-93, 1990. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

Lee, V. H., et al. Biopharmaceutics of transmucosal peptide and protein drug administration role of transport mechanisms with a focus on the involvement of PepTl. J. Control. Release 1999, 62, 129-140. 

Borst, P., et al. A family of drug transporters the multidrug resistance-associated proteins. J. Natl. Cancer Inst. 2000, 92, 1295-1302. 

The identities and roles of many of the drug transporters are discussed in other chapters in this volume, and are not extensively reintroduced here. A goal is to develop a comprehensive panel of cells expressing individual, functional transporters as research reagents. To simplify data interpretation, the set of transporters should be expressed in the same host cell line and the abundance of functional proteins in the cell line should be known relative to the corresponding in vivo values. However, useful mechanistic data can be obtained from less comprehensive systems. 

---