Most drugs are taken by mouth and, in order to be absorbed through the stomach and intestine, they need to be lipid-soluble. This solubility permits them to easily cross the membrane barrier. After absorption, organs with plentiful blood-flow such as the brain, liver, lungs, and kidneys are first exposed to the drug. Only highly lipid-soluble drugs can enter the brain by crossing the blood-brain barrier.
Drug concentration at the target organ is an important index for therapy and generally has an optimal range. The drug level can be raised by increasing dose, or by more frequent administration, but too high a level could cause toxicity. The drug level at the target organ can also be lowered by elimination through the urine or by metabolic steps that convert the drug to more water-soluble forms. Water-soluble metabolites are eliminated quickly in the urine. Most drugs given orally are lipid-soluble enough to be reabsorbed in the kidneys and are eliminated only slowly in small amounts in the unchanged form in urine (see Figure 1). Therefore drug metabolism is an important factor that controls drug levels in the body, because without the metabolic step the drug usually remains in the body or accumulates if it continues to be taken. Drug metabolism is a biochemical process and involves enzymes; drugs are metabolized sequentially or by parallel pathways to various products called metabolites. Many enzymes have been identified and some are very specific for drugs or substrates, whereas others have broad or less stringent structure requirements (see Table 1).
Many factors can modify drug metabolism. Genetic factors or inherited deficiency of an enzyme could cause accumulation of certain drugs. Increased levels and increased toxicity may be caused by inhibition of drug metabolism by other concurrently administered drugs. Decreased plasma levels of drugs after repeated administration have been observed and this is attributed to increased enzyme activity by a process called induction; auto-induction causes the increased metabolism of the inducing drug and cross-induction refers to the accelerated metabolism of other drugs.
Drug-metabolizing enzymes change the chemical nature of drugs by inserting oxygen, hydrogen, water, or small molecules such as amino acids and sugar molecules. The resulting metabolites may thus contain hydroxyl (the univalent group or ion OH), or hydrogenated or hydrolysis products, or be conjugated with sugar or other functional groups. By far the most commonly occurring metabolic step is hydroxylation (the addition of oxygen) by the enzyme oxygenase—and this will be discussed in detail.
OXIDATION BY CYTOCHROME P450 MONOOXYGENASE
Oxygen is vital for living organisms, and enzymatic reactions involving this molecule for drug metabolism are numerous and well characterized. Lipid-solubility is an important factor for absorption across the stomach and intestinal wall, and the insertion of an oxygen atom to lipid-soluble compounds results in hydroxylated groups (-OH) that are more water-soluble than the parent compound. The pioneering work on the oxygenation reaction involved the metabolism of Barbiturates, a class of centrally acting drugs very popular in the 1950s. A long-acting barbiturate, Phenobarbital, very slowly hydroxylates compared to other barbiturates, such as hexobarbital, pentobarbital, and secobarbital. The oxygenation enzymes involved were named cytochrome P450 after the wavelength of light they absorbed in a spectrophotometer (P eak at 450 nanometers [nm]). Subcellular fractionation by centrifugation yielded "microsome" pellets which contained the cytochrome P450 activity. Cytochrome P450 is most abundant in the liver and, before the full nature of cytochrome P450 was known, the microsomal oxygenase was often called mixed function oxidase. Cytochrome P450 consists of a superfamily of enzymes, with wide and sometimes overlapping substrate specificities.
Although phenobarbital is no longer widely used for therapeutic purposes, because of better alternatives with fewer side effects, it is an excellent inducer of certain forms of cytochrome P450 (e.g., the CYP2B family).
Other important drugs of abuse that are metabolized by cytochrome P450 include Benzodiazepines (tranquilizers such as Diazepam [Valium], Chlordiazepoxide, alprazolam, triazolam) and Opioids (Codeine, oxycodone, dextromethorphan). The first group of drugs is hydroxylated and the second group is metabolized by loss of a carbon moiety (dealkylation). The dealkylation reactions are also mediated by cytochrome P450.
Many cytochrome P450 enzymes have been isolated and characterized. With molecular biology techniques, the genetic code DNA has been identified for many cytochrome P450 enzymes. Among these, two forms of cytochrome P450 are known to be deficient in certain individuals. In the mid-1970s, a deficiency of the specific cytochrome P450 called CYP2D6 was independently reported for sparteine (a labor-inducing or antiarrhythmic drug) and for debrisoquine (an antihypertensive agent). Since then, more than thirty clinically useful drugs have been shown to be metabolized by this enzyme. The presence of this cytochrome P450 in a population is polymorphic, that is, some people lack this enzyme. A simple urine test using dextromethorphan, a cough suppressant, is commonly used to identify the enzyme deficiency in a patient. Another cytochrome P450 deficiency involves metabolism of mephenytoin (CYP2C type) but not many drugs are metabolized by this enzyme. The frequency of both deficiencies were first established in Caucasians, and CYP2D6 deficiency was reported to be 7 percent while CYP2C deficiency was 3 percent. Because of the presence of deficient subjects, the population data do not show a bell-shaped normal distribution curve but rather a bimodal distribution indicating polymorphism.
Alcohol (ethanol) metabolism predominantly involves a type of oxidation called dehydrogenation (loss of hydrogen) and the subcellular fraction called the mitochondria is the major site. Alcohol is metabolized by successive dehydrogenation steps, first producing acetaldehyde and secondly acetic acid. The major organ for alcohol metabolism is the liver. In heavy drinkers, however, alcohol induces another enzyme, cytochrome P450, and the proportion of the metabolism by this route compared to dehydrogenation becomes significant. Because the amount of alcohol ingested must be relatively large to have pharmacological effects, the amount of alcohol exceeds the amount of enzyme, resulting in saturation. Acetaldehyde, in general, is toxic because it is reactive and forms a covalent bond with proteins. When the enzyme that metabolizes acetaldehyde to acetic acid is inhibited by an external agent, acetalaldehyde levels increase and produce a toxic syndrome. Inhibitions of this enzyme, such as Disulfiram (Antabuse), have been used in the treatment of excessive drinking.
TRANSFERASES FOR CONJUGATION/SYNTHETIC REACTIONS
Products formed by oxidation (e.g., by cytochrome P450) are often metabolized further with small molecules such as glucuronic acid (glucose metabolite) or sulphate. The enzymes involved are called transferases. Other conjugation reactions are carried out by transferases linking glutathione with reactive metabolic products, acetyl-CoA with an amino group on aromatic rings, and glycine (amino acid) with salicylate.
Glucuronic-acid conjugations are catalyzed by various forms of glucuronyl transferases, which appear to have broad substrate specificity. Glucuronide conjugates are very water-soluble and likely to be quickly eliminated via the kidneys. The plasma levels of glucuronide conjugates of oxazepam (a benzodiazepine antianxiety agent) are, however, several-fold higher than the parent drug. This can be explained by the relatively rapid process of conjugation reaction in the liver compared to the renal (kidney) clearance of its conjugate. Because glucuronidation involves a glucose metabolite, which is abundant, the transferase would not reach saturation easily, although sulfo-transferase utilizes the sulphate which is of limited supply via foods and can be saturated. For example, Acetaminophen (Tylenol) forms both glucuronide and sulfate conjugates and the sulfation process can be easily saturated after a few tablets.
Glutathione conjugation is very important as a detoxification pathway. Unstable or reactive metabolites formed from other metabolic reactions may cause toxicity by reacting with so-called house-keeping enzymes in the body. Glutathione, because of its abundance, can react with these metabolites instead and acts as a scavenger; an epoxide whose formation is catalyzed by cytochrome P450 is detoxified, except in an overdose case, by glutathione transferase. Some epoxide intermediary metabolites have been shown to be ultimate carcinogens, and detoxification by gluthione would be beneficial.
Glycine is the smallest amino acid and the conjugation with salicylic acid (formed rapidly from aspirin) is the major metabolic pathway for salicylates. Salicylate poisoning, especially in children, was very common before the introduction of the child-proof cap for drug containers in the 1960s. The difficulty of treating the salicylate poisoning was due to saturable glycine conjugation; the higher the dose, the slower was the rate of elimination.
Acetylation is also important for the detoxification of carcinogens containing aromatic amines. One form of N-acetyltransferase is polymorphic (people have different forms of the enzyme). The frequency of slow acetylator types shows a large variation ranging from 5 to 10 percent in Oriental and Inuit (Eskimo) subjects to as high as 50 percent in Caucasians and Africans. Drugs affected by this genetic polymorphism are isoniazid (antituberculosis), procainamide (antiarrhythmic), sulfa-methazole (antibiotic), and other amine-containing compounds.
Drug metabolites are often pharmacologically less active than the parent drug. Yet some biotransformation products are active—for example Co-Deine is relatively inactive but is metabolized to the active drug Morphine. Because the liver is the major site of drug metabolism, acute or chronic liver diseases would alter drug metabolism, resulting in prolonged drug half-lives and effects.
(See also: Complications: Liver (Alcohol) ; Drug Interaction and the Brain ; Drug Interactions and Alcohol )
Jakoby, W. B. (Ed.). (1980). Enzymatic basis of detoxication. New York: Academic Press.
Kalow, W. (Ed.). (1992). Pharmacogenetics of drug metabolism. New York: Pergamon.
Katsung, B. G. (Ed.). (1992). Basic and clinical pharmacology, 5th edition. Norwalk, CT: Appleton & Lange.
Revised by Mary Carvlin
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