Τόμος 6 (1988) – Τεύχος 4 – Άρθρο 3- Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Ελληνική Έκδοση – Volume 6 (1988) – Issue 4 – Article 3 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-Greek Edition

A.S. TSIFTSOGLOU AND L.C. PAPADOPOULOU

6: 227-242 (1988)

PHARMAKON-Press: Epitheorese Klin. Farmakol. Farmakokinet.

6: 227-242 (1988)

It is well known that for a given drug that is administered into the body in order to produce its pharmacological effects, the drug must reach its site of action at appropriate concentration. This depends upon the extent at which the drug is absorbed into the body, distributed into the plasma and other tissues, metabolized and excreted. Absorption, distribution, metabo­lism and excretion of the drugs, all involve transport of the drugs across the biological membranes. This article describes the basic architectural structure of biological membranes of eukaryotic cells and pre­sents the mechanisms by which drugs cross the plasma membrane and enter the cells, where they act at intracellular target sites (DNA, RNA or proteins). Transport across the plasma membrane can occur either by passive diffusion, where the rate is deter­mined by the differences in drug concentra­tion (outside and inside the cell) and electrochemical gradient or by protein carrier-mediated processes, which can be either facilitated diffusion or active trans­port. The latter process depends highly on energy sources. In all cases, the rate of drug transport is influenced by the physicoche­mical properties of the drug (lipophilic agents cross the plasma membrane easily while hydrophilic or charged molecules need a specific transport system to enter the cells). The article also describes the mecha­nism by which macromolecules enter the cells by endocytosis. Carrier-proteins are often transmembrane proteins which inter­act selectively with molecules and transfer them into the intracellular space. In some occasions, transmembrane proteins form channels which facilitate transport of ions (Na⁺, Κ⁺, Ca⁺⁺) into the cells (channel proteins). In addition to the class of the carrier-proteins, a number of cellular pro­teins localized either on plasma membrane or intracellularly serve as receptors for drugs, neurotransmitters and hormones in a manner that determines the magnitude of their pharmacological activity. Therefore, several drug interactions can be seen as changes in drug transport where one drug alters the rate of transport of another drug or as changes at the level of the receptor or target site, where one drug counteracts the action of another drug by preventing its binding to a cellular protein. Α good example of such drug interaction represents the ability of hemin (iron protoporphyrin IX) to counteract the cytotoxic effects of adriamycin and of other anthracyclines [daunomycin (DAU), aclacinomycin etc.] in a number of normal and transformed hemo­poletic cells. Experimental evidence exists to indicate that hemin decreases both the rate of transport and intracellular net accumulation of [³H(G)]-DΑU and subse­quently prevents [³Η(G)]-DΑU to interact and bind with intracellular proteins.

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