Pharmaceutical biotechnology最新文献

P-glycoprotein was initially isolated due to its role in multidrug resistance to cancer chemotherapeutics. Recent work, however, makes it increasingly apparent that this transporter is also involved in the pharmacokinetics of many drugs. P-gp is strategically expressed in the luminal epithelial cells of organs often associated with drug absorption and disposition, for example, hepatocyte canalicular membrane, renal proximal tubules, and the intestinal mucosa. P-gp is also expressed in the endothelial cells comprising the blood-brain barrier. This localization clearly suggests the potential for this protein to serve as a protective mechanism against entry of toxic xenobiotics and also suggests that P-gp is well situated to participate in the removal of therapeutic agents. Numerous investigations with drugs such as digoxin, etoposide, cyclosporine, vinblastine, Taxol, loperamide, dom-peridone, and ondansteron demonstrate that P-gp has an important role in determining the pharmacokinetics of substrate drugs. Pharmacological modulation of P-gp function to increase drug bioavailability, both on a organismal and a cellular level, is one approach currently being explored to enhance therapeutic effectiveness. This approach is not without potential collateral consequences given the wide tissue distribution of P-gp. While animals deficient in P-gp are viable and without obvious abnormalities, the pharmacokinetics and toxic consequences of several compounds are significantly altered in these animals. Thus blockade of the protective P-gp barrier in humans may have adverse effects on substrate drugs. In particular, this situation may arise when several compounds which may be substrates compete for P-gp-mediated transport. Additional multidrug transporters, notably MRP and family members, have been identified and may also determine the fate of pharmaceuticals. Further understanding the physiological role of each of the multidrug transporters is critical for determining their role in pharmacokinetics and for evaluating the consequences of modification of their activities. Such information is also important in the development of novel drugs which may be substrates for these transporters.

In this review, we have summarized recent advances in our understanding of the biology of nucleoside transport arising from new insights provided by the isolation and functional expression of cDNAs encoding the major nucleoside transporters of mammalian cells. Nucleoside transporters are required for permeation of nucleosides across biological membranes and are present in the plasma membranes of most cell types. There is growing evidence that functional nucleoside transporters are required for translocation of nucleosides between intracellular compartments and thus are also present in organellar membranes. Functional studies during the 1980s established that nucleoside transport in mammalian cells occurs by two mechanistically distinct processes, facilitated diffusion and Na(+)-nucleoside cotransport. The determination of the primary amino acid sequences of the equilibrative and concentrative transporters of human and rat cells has provided a structural basis for the functional differences among the different transporter subtypes. Although nucleoside transporter proteins were first purified from human erythrocytes a decade ago, the low abundance of nucleoside transporter proteins in membranes of mammalian cells has hindered analysis of relationships between transporter structure and function. The molecular cloning of cDNAs encoding nucleoside transporters and the development of heterologous expression systems for production of recombinant nucleoside transporters, when combined with recombinant DNA technologies, provide powerful tools for characterization of functional domains within transporter proteins that are involved in nucleoside recognition and translocation. As relationships between molecular structure and function are determined, it should be possible to develop new approaches for optimizing the transportability of nucleoside drugs into diseased tissues, for development of new transport inhibitors, including reagents that are targeted to the concentrative transporters, and, eventually, for manipulation of transporter function through an understanding of the regulation of transport activity.