Most drugs must be transferred from their site of administration to the bloodstream in order to reach their target tissues within the body. Drugs administered intravenously are completely absorbed and the total dose of intravenously administered drugs reaches the systemic circulation. But drugs administered other ways may be only partially absorbed. Oral administration is the most common route. It requires that a drug dissolve in the gastrointestinal fluid and then penetrate the epithelial cells of the intestinal mucosa in order to access the bloodstream (Figure 16.1).
Drugs designed to reach the central nervous system must cross the blood-brain barrier formed by endothelial cells that line blood vessels in the central nervous system. These cells form tight junctions that restrict the entry of molecules greater than 400 daltons in size. This barrier is a major obstacle for development of drugs to treat central nervous system disorders including neurodegenerative diseases (such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease), psychiatric illnesses (such as anxiety, depression, and schizophrenia), and stroke and cerebrovascular disorders (Figure 16.2).
FIGURE 16.1. Orally administered drugs must penetrate the epithelial cells of the intestinal mucosa in order to enter the circulation.
FIGURE 16.2. The blood-brain barrier restricts entry of drugs to the central nervous system.
Most drugs are either weak acids or weak bases. Concentrations of permeable forms of drugs are sometimes determined by relative concentrations of their charged and uncharged forms since uncharged molecules are thought to pass through membranes more readily than charged molecules. Studies of relationships of acid and base concentrations to pH have been done to determine the amount of drug that will be found on each side of a membrane (see also LIR Pharmacology, pp. 4–6).
While it has long been assumed that lipid soluble drugs diffuse across cell membranes, barriers to diffusion do exist in the hydrophilic head groups of membrane phospholipids (see also Chapter 13). Some small water soluble molecules may be able to use water channels or pores to cross membranes (Figure 16.3). It is becoming increasingly recognized that transport proteins facilitate the movement of drugs across biological membranes. Active transport processes appear to be most commonly used by drugs.
FIGURE 16.3. Mechanisms of drug crossing the intestinal epithelial cells.
CLASSES OF DRUG TRANSPORTERS
Many drug transporters function as primary and secondary active transporters (see Chapter 15 for a discussion of active transport). Based on sequence similarities, drug transporters have been classified as solute carriers (SLCs) and ATP-binding cassette (ABC) transporters (Figure 16.4). The structures, functions, and tissue distributions of drug transporters within each group can vary widely.
FIGURE 16.4. Drug transporters include SLCs and ABC transporters.
The SLCs are classified into four major families: peptide transporters (PEPT), organic anion-transporting polypeptides (OATP), organic ion transporters, and H+/organic cation antiporters.
- Peptide transporters: Protons (H+) and peptides are cotransported by PEPT proteins that transport small peptides (two and three amino acids) but not individual amino acids or larger peptides. These are responsible for transporting drugs such as ?-lactam antibiotics (including penicillin) and ACE inhibitors (angiotensin converting enzyme inhibitors, used to treat hypertension) across the intestinal epithelium. In order to increase absorption of certain anticancer and antiviral drugs, some are being converted into better PEPT substrates by modification of their amino acid sequences.
- Organic anion-transporting polypeptides: These transporters catalyze the movement of amphipathic organic compounds such as bile salts, steroids, and thyroid hormones. One member of this family, OATP1B1, is responsible for hepatic (liver) uptake of pravastatin, an inhibitor of cholesterol synthesis, and of the ACE inhibitor enalapril. Individual genetic variations in OATP1B1, known as gene polymorphisms, cause altered transport of pravastatin and differences in individual patients’ responses to the drugs.
- Organic ion transporters: This family makes up a large group of drug transporters. Some are uniporters while others are symporters or antiporters. Various members of this family are expressed in liver, kidney, skeletal muscles, and the intestinal brush border. Renal secretion of drugs and toxins is mediated in part by organic ion transporters. The drug metformin (a hypoglycemic agent used to treat elevated blood glucose in type 2 diabetes) is taken up by a transporter in this family.
- H+/organic cation antiporters: Organic cations are excreted by the proton/organic cation antiporter in brush border membranes. An oppositely directed proton gradient is the driving force of the transport.
These ATP-binding proteins that use primary active transport are responsible for exporting ions, drugs, and xenobiotics from cells (see also Chapter 15). There is a growing list of substrates of ABC transporters including anticancer agents, antiviral agents, calcium channel blockers, and immunosuppressive agents. Multidrug resistance (MDR) can develop when cells expel the therapeutic agents designed to inhibit or kill them (Figure 16.5). Cancer cells that develop MDR do not respond to chemotherapy. Inhibitors of ABC transporters are being explored as a way to prevent MDR. ABCB1 or P-glycoprotein (P-gp) is an ABC transporter often implicated in MDR and is responsible for extruding chemotherapeutic agents from cancer cells.
ABCB1 is also expressed in normal tissues. For example, in the intestinal epithelial brush border, ABCB1 is responsible for the efflux of xenobiotics before they reach the circulation. Herbals such as St. John’s wort and the antituberculosis drug rifampin are known to induce intestinal expression of ABCB1. Such increased expression decreases the absorption of ABCB1 substrates such as digoxin (used to increase heart muscle contraction and to decrease heart rate) because these drugs are exported by ABCB1 that is expressed at higher levels on the intestinal epithelial cells.
FIGURE 16.5. Development of MDR.
- Drugs administered by the oral route must cross barriers presented by plasma membranes in the intestinal epithelium in order to be absorbed into the blood circulation.
- Endothelial cells lining blood vessels in the central nervous system form a blood-brain barrier to drugs aimed at the central nervous system.
- While passive diffusion has long been described as a mechanism of drug transport into cells, the plasma membranes of these cells represent a barrier to diffusion.
- Drug transport proteins are being identified on many cell types in the body.
- Drug transport proteins include SLCs and ABC transporters.
- Many drug transporters use active transport, either primary or secondary.
- While SLCs transport drugs into cells, ABC transporters export drugs and xenobiotic compounds from cells.
- ABC transporters mediate MDR that develops when cells expel drugs designed to inhibit or kill them, such as cancer cells exporting chemotherapy agents.