Concentration gradient-dependent facilitated transport

The transport mechanisms that operate in distribution and elimination processes of drugs, drug-carrier conjugates and pro-drugs include convective transport (for example, by blood flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in the case of macromolecules, endocytosis. The kinetics of the particular transport processes depend on the mechanism involved. For example, convective transport is governed by fluid flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion, active transport and endocytosis obey saturable MichaeUs-Menten kinetics. 

Facilitated transport is not energy dependent, and therefore, cannot move a substance against a concentration gradient, as in active transport. The direction in which the substance moves across the membrane depends upon the difference in the substance s concentration between the exterior and interior of the cell transport across the membrane occurs in the direction of higher to lower concentration of substance. Facilitated transport is stereospecific. 

Both facilitated and simple diffusion depend on concentration gradients net solute transport always occurs from high to low concentration. Unlike diffusion, facilitated transport systems are specific, since they depend on binding of the solute to a site on the transport protein. For example, the D-glucose... 

Facilitated transport combines some properties of both mechanisms discussed above. This type of transport is carrier mediated so that there is substrate specificity, a transport maximum, and competitive inhibition. However, facilitated transport is not energy-dependent and is unable to transport a substrate against a concentration gradient. 

Anandamide is inactivated in two steps, first by transport inside the cell and subsequently by intracellular enzymatic hydrolysis. The transport of anandamide inside the cell is a carrier-mediated activity, having been shown to be a saturable, time- and temperature-dependent process that involves some protein with high affinity and specificity for anandamide (Beltramo, 1997). This transport process, unlike that of classical neurotransmitters, is Na+-independent and driven only by the concentration gradient of anandamide (Piomelli, 1998). Although the anandamide transporter protein has not been cloned yet, its well characterized activity is known to be inhibited by specific transporter inhibitors. Reuptake of 2-AG is probably mediated by the same facilitating mechanism (Di Marzo, 1999a,b Piomelli, 1999). 

Several mechanisms for the transport of ions are operative (1) active transport of the ion against a concentration gradient by an ATP-driven membrane carrier, (2) passive carrier facilitated transport, (3) passive diffusion dependent upon the abihfy of the ion or complex to pass the membrane. Sodium,... 

The placenta keeps the maternal and fetal circulation systems separate, nourishes the fetus, eliminates fetal wastes, and produces hormones vital to pregnancy. It is composed of large collections of fetal vessels called villi, which are surrounded by intervillous spaces in which maternal blood flows. For substances to move from maternal circulation to fetal circulation, they must cross through the trophoblasts and several membranes. The transfer of any substance depends largely on the concentration gradient between the maternal and fetal circulatory systems, the presence or absence of circulating binding proteins, the hpid solubility of the substance, and the presence of facilitated transport, such as ion pumps or receptor-mediated endocytosis (Box 54-1). The placenta is an effective barrier to the movement... 

Hemodialysis consists of the perfusion of blood and a physiologic salt solution on opposite sides of a semipermeable membrane. Multiple substances, such as water, urea, creatinine, uremic toxins, and drugs move from the blood into the dialysate, thus facilitating removal from the blood. Solutes are transported across the membrane by either passive diffusion or ultraflltration. Diffusion is the movement of substances along a concentration gradient, the rate of diffusion depends on the difference between the concentrations of solute in blood and dialysate, solute characteristics, the dialyzer composition, and flow rates (blood and dialysate). Ultraflltration is the movement of water across the membrane due to hydrostatic or osmotic pressure, and is the primary means for removal of excess body water. Convection (expressed as mL of plasma water removed per hour per mm of mercury of pressure within the dialyzer) occurs... 

A drug s ability to permeate is dependent on its solubility, the concentration gradient, and the available surface area, which is influenced by the degree of vascularity. Ionization affects permeation because unionized molecules are minimally water soluble but do cross biomembranes, a feat beyond the capacity of ionized molecules. Figure I-1-2 illustrates the principles associated with ionization, and Table 1-1 -2 summarizes the three basic modes of transport across a membrane passive, facilitated, and active. 

In facilitated transport of metal ions through LM, the metal ions are transported through the membrane against their own concentration gradient, termed as the uphill transport. The driving force in such processes is provided by the chemical potential difference of the species other than the diffusing ones on either side of the membrane. The permeability of the transported species is decided by the parameters such as membrane thickness, pore structure, aqueous diffusion coefficient of the species, aqueous diffusion layer thickness, and distribution and diffusion coefficients of the transported species in the LM phase. The diffusion of the species in the carrier solvent depends on the membrane characteristics (viz., porosity and tortuosity) and viscosity of the solvent, while the aqueous diffusion of the metal ions depends upon the flow rate and diffusivity of metal species in the aqueous phase. On the other hand, the overall transport rates of the species can be controlled through various parameters such as feed composition, carrier concentration, and receiver phase composition. 

The mechanism of DHAA uptake by luminal membranes of human jejunum has pharmacological characteristics that clearly differ from those of ascorbate uptake. Sodium-independent carriers take up DHAA by facilitated diffusion, and these are distinct from the sodium-dependent transporters of ascorbate. Glucose inhibits ascorbate uptake but not DHAA uptake, which raises the possibility that glucose derived from food may increase the bioavailability of DHAA relative to ascorbate (Malo and Wilson, 2000). Human enterocytes contain reductases that convert DHAA to ascorbate (Buffinton and Doe, 1995). This conversion keeps the intracellular level of DHAA low, and the resulting concentration gradient favors uptake of oxidized AA across the enterocyte plasma membrane. 

---