Basic Mechanisms Of Membrane Transport Transporters Versus Channels

Both channels and transporters facilitate the membrane permeation of inorganic ions and organic compounds. Channels have two primary states, open and closed, that are stochastic phenomena. Only in the open state do channels act as pores for their selected ions, allowing permeation across the plasma membrane. After opening, channels return to the closed state as a function of time.

Blood

Blood

FIGURE 2-2 Hepatic drug transporters. Membrane transporters, shown as hexagons with arrows, work in concert with phase 1 and phase 2 drug-metabolizing enzymes in the hepatocyte to mediate the uptake and efflux of drugs and their metabolites.

FIGURE 2-3 Major mechanisms by which transporters mediate adverse drug responses. Three cases are given. The left panel of each case provides a cartoon representation of the mechanism; the right panel shows the resulting effect on drug levels. (Top panel) Increase in the plasma concentrations of drug due to a decrease in the uptake and/or secretion in clearance organs such as the liver and kidney. (Middle panel) Increase in the concentration of drug in toxicological target organs due either to the enhanced uptake or to reduced efflux of the drug. (Bottom panel) Increase in the plasma concentration of an endogenous compound (e.g., a bile acid) due to a drug's inhibiting the influx of the endogenous compound in its eliminating or target organ. The diagram also may represent an increase in the concentration of the endogenous compound in the target organ owing to drug-inhibited efflux of the endogenous compound.

FIGURE 2-3 Major mechanisms by which transporters mediate adverse drug responses. Three cases are given. The left panel of each case provides a cartoon representation of the mechanism; the right panel shows the resulting effect on drug levels. (Top panel) Increase in the plasma concentrations of drug due to a decrease in the uptake and/or secretion in clearance organs such as the liver and kidney. (Middle panel) Increase in the concentration of drug in toxicological target organs due either to the enhanced uptake or to reduced efflux of the drug. (Bottom panel) Increase in the plasma concentration of an endogenous compound (e.g., a bile acid) due to a drug's inhibiting the influx of the endogenous compound in its eliminating or target organ. The diagram also may represent an increase in the concentration of the endogenous compound in the target organ owing to drug-inhibited efflux of the endogenous compound.

In contrast, a transporter forms an intermediate complex with the substrate (solute); thereafter, a conformational change in the transporter induces substrate translocation to the other side of the membrane. Because of these different mechanisms, turnover rates differ markedly between channels and transporters. Turnover rate constants of typical channels are 106-1(f s-1, whereas those of transporters are, at most, 101-103 s-1. Because transporters form intermediate complexes with specific compounds, transporter-mediated membrane transport is characterized by saturability and inhibition by substrate analogs.

The basic mechanisms involved in solute transport across the plasma membrane include passive diffusion, facilitated diffusion, and active transport. Active transport can be further subdivided into primary and secondary active transport. These mechanisms are depicted in Figure 2-4.

Passive transport (downhill transport)

Active transport {uphill transport)

Electrochemical potential HiSh gradient ot the substrate

Passive diffusion

Electrochemical potential HiSh gradient ot the substrate

Passive diffusion

Electrochemical potential ' gradient of the substrate ow

O Symport

O Antiport

ATP Primary active transport

FIGURE 2-4 Classification of membrane transport mechanisms. Light blue circles depict the substrate. Size of the circles is proportional to the concentration of the substrate. Arrows show the direction of flux. Black squares represent the ion that supplies the driving force for transport (size is proportional to the concentration of the ion). Dark blue ovals depict transport proteins.

O Symport

O Antiport

Secondary active transport

PASSIVE DIFFUSION Simple diffusion of a solute across the plasma membrane involves three processes: partition from the aqueous to the lipid phase, diffusion across the lipid bilayer, and repartition into the aqueous phase on the opposite side. Diffusion of any solute (including drugs) occurs down an electrochemical potential gradient of the solute and is dependent on both its chemical and electrical potential.

FACILITATED DIFFUSION Membrane transporters may facilitate diffusion of ions and organic compounds across the plasma membrane; this facilitated diffusion does not require energy input. Just as in passive diffusion, the transport of ionized and nonionized compounds across the plasma membrane occurs down their electrochemical potential gradient. Therefore, steady state will be achieved when the electrochemical potentials of the compound on both sides of the membrane become equal.

ACTIVE TRANSPORT Active transport requires energy input and transports solutes against their electrochemical gradients, leading to the concentration of solutes on one side of the plasma membrane and the creation of potential energy in the electrochemical gradient formed. Active transport plays an important role in the uptake and efflux of drugs and other solutes. Depending on the driving force, active transport can be subdivided into primary and secondary active transport (Figure 2-4).

Primary Active Transport Membrane transport that directly couples with ATP hydrolysis is called primary active transport. ABC transporters are examples of primary active transporters. They contain one or two highly conserved ATP binding cassettes that exhibit ATPase activity. ABC transporters mediate the unidirectional efflux of many solutes across biological membranes.

Secondary Active Transport In secondary active transport, the transport across the plasma membrane of one solute Sj against its concentration gradient is driven energetically by the transport of another solute S2 in accordance with its concentration gradient. The driving force for this type of transport therefore is stored in the electrochemical potential created by the concentration difference of S2 across the plasma membrane. Depending on the transport direction of the solute, secondary active transporters are classified as either symporters or antiporters. Symporters, also termed cotransporters, transport S2 and Sj in the same direction, whereas antiporters, also termed exchangers, move their substrates in opposite directions (Figure 2-4).

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