A General Overview The primary function of transporters is to transport endogenous substances, such as hormones, glucose, and amino acids; however, many of these transporters also transport xenobiotics. It is these drug transporters that are of importance when considering drug disposition and drug response. Drug transporters are localized to barrier membranes of the body responsible for xenobiotic entry and exit. They are expressed in organs of absorption, such as the intestine, and clearance organs including the liver and kidney. Transporters are also expressed on membranes that separate particularly susceptible organs from the rest of the body, including the blood–brain and blood–placenta barriers, where they facilitate the influx of nutrients and efflux of potentially harmful xenobiotics. Because of their location on barrier membranes, transporters have an important role in drug pharmacokinetics and pharmacodynamics. Transporters can have a role in drug absorption and can facilitate or prevent drug entry into the body.

A General Overview The role of transporters in drug distribution can also affect drug response by allowing or preventing drug access to the site of action. One of the most interesting roles of drug transporters is their indirect effects on drug metabolism. Transporters can restrict or allow a drug’s distribution into organs that contain drug-metabolizing enzymes, particularly the liver and the intestine. In this regard, there can be extensive transport-metabolism interplay, and transport or metabolism can be the rate-limiting process controlling drug elimination. Transporters are also responsible for transport and removal of drug metabolites. Transporters have a significant role in drug excretion, as they are present in the kidney and on the canalicular membrane of the liver where they can facilitate drug elimination into the urine or bile, respectively.

MECHANISMS OF MEMBRANE TRANSPORT Transport mechanisms most commonly used by therapeutic agents include passive diffusion and facilitated transport.

MECHANISMS OF MEMBRANE TRANSPORT Passive diffusion is the simplest way for a drug to pass through a membrane and depends only on the existence of a concentration gradient for a molecule across the membrane. Because of the lipophilicity of biologic membranes, diffusion is energetically unfavorable for drugs that are relatively hydrophilic, particularly for drugs that are predominantly ionized at physiologic pH, and these molecules require facilitated transport. Facilitated transport refers to any transport aided by a facilitating protein. Similar to diffusion, passive facilitated transport depends only on the existence of a concentration gradient and involves movement of molecules down this gradient. Active transport uses a separate energy source to move molecules against their concentration gradient. Drug transporters can use either passive or active transport mechanisms. Paracellular transport (transfer of substances between cells of an epithelial cell layer) and transcytosis (vesicular transfer of substances across the interior of a cell) are less commonly used mechanisms of membrane transport. Molecules can use one or more of these mechanisms to cross biological membranes.

CLASSIFICATION OF TRANSPORTERS Facilitative Versus Active Transporters

CLASSIFICATION OF TRANSPORTERS Primary Versus Secondary Active Transporters Primary active transporters most commonly use adenosine triphosphate (ATP) as an energy source for substrate transport. Secondary active transporters use the concentration gradient of another substance, such as protons or sodium ions, but also other ionic endogenous substances as energy sources to drive transport.

CLASSIFICATION OF TRANSPORTERS Primary Versus Secondary Active Transporters Types of drug transporters. Primary active transporters use ATP and have the ability to transport substrates against their concentration gradient. Secondary active transporters used gradients created by primary active transport to transport drug substrates. Facilitated transporters only transport substrates down their concentration gradient. Transporters that transport drug substrates are shown in red, whereas those shown in gray provide driving forces for drug transport. The same direction, referred to as symport, or in opposite directions, referred to as antiport.

CLASSIFICATION OF TRANSPORTERS Influx Versus Efflux Transporters Influx transporters transport substrates from extracellular spaces into cells. Efflux transporters transport substrates out of cells. Transporters are usually responsible for either drug influx or drug efflux, but in some cases facilitate both types of transport. CLASSIFICATION OF TRANSPORTERS Secretory Versus Absorptive Transporters Secretory transporters facilitate drug clearance and are responsible for transport of drugs from the blood, such as excretion into the urine. Absorptive transporters allow a drug access into the blood, such as those facilitating absorption in the gut or reabsorption in the kidney. A transporter can be both secretory and absorptive depending on its physiologic locations.