Many cells also contain less selective membrane carriers that are specialized for expelling foreign molecules.One large family of such transporters bind adenosine triphosphate(ATP)and is called the ABC (ATP-binding cassette)family.This family includes the P-glycoprotein or multidrug-resistance type 1(MDRI)transporter found in the brain,testes,and other tissues, and in some drug-resistant neoplastic cells.Similar transport molecules from the ABC family,the multidrug resistance-associated protein (MRP1 through MRP5)transporters,play important roles in excretion of some drugs or their metabolites into urine and bile and in resistance of some tumors to chemotherapeutic drugs.Several other transporter families have been identified that do not bind ATP but use ion gradients for transport energy.Some of these are particularly important in the uptake of neurotransmitters across nerve ending membranes. 4.Endocytosis and exocytosis-A few substances are so large or impermeant that they can enter cells only by endocytosis,the process by which the substance is engulfed by the cell membrane and carried into the cell by pinching off of the newly formed vesicle inside the membrane.The substance can then be released inside the cytosol by breakdown of the vesicle membrane.This process is responsible for the transport of vitamin B12,complexed with a binding protein(intrinsic factor)across the wall of the gut into the blood.Similarly,iron is transported into hemoglobin-synthesizing red blood cell precursors in association with the protein transferrin. Specific receptors for the transport proteins must be present for this process to work. The reverse process (exocytosis)is responsible for the secretion of many substances from cells For example,many neurotransmitter substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cytoplasm.Appropriate activation of the nerve ending causes fusion of the storage vesicle with the cell membrane and expulsion of its contents into the extracellular space(see Chapter 6). "The capillaries of the brain,the testes,and some other tissues are characterized by the absence of pores that permit aqueous diffusion.They may also contain high concentrations of drug export pumps (MDR pumps;see text).These tissues are therefore protected or "sanctuary"sites from many circulating drugs. B.FICK'S LAW OF DIFFUSION The passive flux of molecules down a concentration gradient is given by Fick's law: where Ci is the higher concentration,C2 is the lower concentration,area is the area across which diffusion is occurring,permeability coefficient is a measure of the mobility of the drug molecules in the medium of the diffusion path,and thickness is the thickness (length)of the diffusion path.In the case of lipid diffusion,the lipid:aqueous partition coefficient is a major determinant of mobility of the drug because it determines how readily the drug enters the lipid membrane from the aqueous medium.Many cells also contain less selective membrane carriers that are specialized for expelling foreign molecules. One large family of such transporters bind adenosine triphosphate (ATP) and is called the ABC (ATP-binding cassette) family. This family includes the P-glycoprotein or multidrug-resistance type 1 (MDR1) transporter found in the brain, testes, and other tissues, and in some drug-resistant neoplastic cells. Similar transport molecules from the ABC family, the multidrug resistance-associated protein (MRP1 through MRP5) transporters, play important roles in excretion of some drugs or their metabolites into urine and bile and in resistance of some tumors to chemotherapeutic drugs. Several other transporter families have been identified that do not bind ATP but use ion gradients for transport energy. Some of these are particularly important in the uptake of neurotransmitters across nerve ending membranes. 4. Endocytosis and exocytosis A few substances are so large or impermeant that they can enter cells only by endocytosis, the process by which the substance is engulfed by the cell membrane and carried into the cell by pinching off of the newly formed vesicle inside the membrane. The substance can then be released inside the cytosol by breakdown of the vesicle membrane. This process is responsible for the transport of vitamin B12, complexed with a binding protein (intrinsic factor) across the wall of the gut into the blood. Similarly, iron is transported into hemoglobin-synthesizing red blood cell precursors in association with the protein transferrin. Specific receptors for the transport proteins must be present for this process to work. The reverse process (exocytosis) is responsible for the secretion of many substances from cells. For example, many neurotransmitter substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cytoplasm. Appropriate activation of the nerve ending causes fusion of the storage vesicle with the cell membrane and expulsion of its contents into the extracellular space (see Chapter 6). *The capillaries of the brain, the testes, and some other tissues are characterized by the absence of pores that permit aqueous diffusion. They may also contain high concentrations of drug export pumps (MDR pumps; see text). These tissues are therefore protected or "sanctuary" sites from many circulating drugs. B. FICK'S LAW OF DIFFUSION The passive flux of molecules down a concentration gradient is given by Fick's law: where C1 is the higher concentration, C2 is the lower concentration, area is the area across which diffusion is occurring, permeability coefficient is a measure of the mobility of the drug molecules in the medium of the diffusion path, and thickness is the thickness (length) of the diffusion path. In the case of lipid diffusion, the lipid:aqueous partition coefficient is a major determinant of mobility of the drug, because it determines how readily the drug enters the lipid membrane from the aqueous medium