General Principles Of Pharmacology:Drug metabolism: some definitions and explanatory notes
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Xenobiotics: a "foreign" compound, which may be a drug or environmentally distributed chemical.
Detoxification: decreased activity following metabolism or biotransformation (note that metabolism does not always result in decreased activity).
Metabolism: often used to refer exclusively to normal anabolic and catabolic reactions of the body (protein, fat, carbohydrate, nucleic acids) but can refer to the chemical transformation of xenobiotics.
Biotransformation: the chemical transformation of xenobiotics.
Renal excretion plays a pivotal role in terminating the biologic activity of a few drugs, particularly those that have small molecular volumes or possess polar characteristics such as functional groups fully ionized at physiologic pH.
Pharmacologically active organic molecules tend to be lipophilic and remain unionized or only partially ionized at physiologic pH. They are often strongly bound to plasma proteins. Such substances are not readily filtered at the glomerulus. The lipophilic nature of renal tubular membranes also facilitates the reabsorption of hydrophobic compounds following their glomerular filtration.
Consequently, most drugs would have a prolonged duration of action if termination of their action depended solely on renal excretion. An alternative process that may lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excretable products. Metabolic products are often less active than the parent drug and may even be inactive.
However, some biotransformation products have enhanced activity or toxic properties, including mutagenicity (induce heritable alteration of DNA), teratogenicity (production of birth defects), and carcinogenicity (cause cellular transformation). This observation undermines the once popular theory that drug-biotransforming enzymes evolved as a biochemical defense mechanism for the detoxification of environmental xenobiotics. The synthesis of endogenous substrates such as steroid hormones, cholesterol, and bile acids involves many enzyme-catalyzed pathways associated with the metabolism of xenobiotics. The same is true of the formation and excretion of endogenous metabolic products such as bilirubin, the end catabolite of heme.
Finally, drug-metabolizing enzymes have been exploited through the design of pharmacologically inactive pro-drugs that are converted in vivo to pharmacologically active molecules. Most metabolic biotransformations occur at some point between absorption of the drug into the general circulation and its renal elimination. A few transformations occur in the intestinal lumen (bacterial activity) or intestinal wall (villi). In general, all of these reactions can be assigned to one of 2 major categories:
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Phase I Reactions or Phase II Reactions
Phase I reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Often these metabolites are inactive, although in some instances activity is only modified. If Phase I metabolites are sufficiently polar, they may be readily excreted.
Many Phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the newly established functional group to form a highly polar conjugate. Such conjugation or synthetic reactions are the hallmarks of Phase II metabolism.
First-Pass Metabolism
Although every tissue has some ability to metabolize drugs, the liver is the principal organ of drug metabolism. Other tissues that display considerable activity include the gastrointestinal tract, the lungs, the skin, and the kidneys.
Following oral administration, many drugs (e.g., isoproterenol, meperidine, pentazocine, morphine) are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism.
This process has been called a first-pass effect. Some orally administered drugs (e.g., clonazepam, chlorpromazine) are more extensively metabolized in the intestine than in the liver. Thus, intestinal metabolism may contribute to the overall first-pass effect.
First-pass effects may so greatly limit the bioavailability of orally administered drugs that alternative routes of administration must be employed to achieve therapeutically effective blood levels.
Cellular Localization
The lower gut harbors intestinal microorganisms that are capable of many biotransformation reactions. In addition, drugs may be metabolized by gastric acid (e.g., penicillin), digestive enzymes (e.g., polypeptides such as insulin), or by enzymes in the wall of the intestine (e.g., sympathomimetic catecholamines).
Although drug biotransformation in vivo can occur by spontaneous, noncatalyzed chemical reactions, the vast majority are catalyzed by specific cellular enzymes. At the subcellular level, these enzymes may be located in the endoplasmic reticulum, mitochondria, cytosol, lysosomes, or even the nuclear envelope or plasma membrane.
Mixed Function Oxidases
Many drug-metabolizing enzymes are located in the lipophilic membranes of the endoplasmic reticulum of the liver and other tissues. When these lamellar membranes are isolated by homogenization and fractionation of the cell, they re-form into vesicles called microsomes. Microsomes retain most of the morphologic and functional characteristics of the intact membranes, including the rough and smooth surface features of the rough (ribosome-studded) and smooth (no ribosomes) endoplasmic reticulum. Whereas the rough microsomes tend to be dedicated to protein synthesis, the smooth microsomes are relatively rich in enzymes responsible for oxidative drug metabolism. In particular, they contain the important class of enzymes known as the mixed function oxidases (MFO), or monooxygenases.
The activity of this enzyme system requires both a reducing agent (NADPH) and molecular oxygen. In a typical reaction, one molecule of oxygen is consumed (reduced) per substrate molecule, with one oxygen atom appearing in the product and the other in the form of water. Two enzymes are important in this process:
NADPH-cytochrome P-450 reductase
One mole of this enzyme (molecular weight of 80,000) contains one mole each of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Because cytochrome c can serve as an electron acceptor, the enzyme is often referred to as NADPH-cytochrome c reductase.
Cytochrome P-450
The name cytochrome P-450 is derived from the spectral properties of this hemoprotein. In its reduced (ferrous) form, it binds carbon monoxide to give a ferrocarbonyl adduct that absorbs maximally in the visible region of the electromagnetic spectrum at 450 nm. Over half of the heme synthesized in the liver is committed to hepatic cytochrome P-450 formation. The relative abundance in liver of cytochrome P-450, as compared to that of the reductase, makes the reductase the rate-limiting step in hepatic drug oxidations.
Microsomal drug oxidations require cytochrome P-450, cytochrome P-450 reductase, NADPH, and molecular oxygen. The cycle involves four steps:
Oxidized (Fe3+) cytochrome P-450 combines with a drug substrate to form a binary complex. NADPH donates an electron to the cytochrome P-450 reductase, which in turn reduces the oxidized cytochrome P-450-drug complex.
A second electron is introduced from NADPH via the same cytochrome P-450 reductase, which serves to reduce molecular oxygen and form an "activated oxygen"-cytochrome P-450-substrate complex.
This complex in turn transfers "activated" oxygen to the drug substrate to form the oxidized product. The potent oxidizing properties of this activated oxygen permit oxidation of a large number of substrates.
Substrate specificity is very low for this enzyme complex. High solubility in lipids is the only common structural feature of the wide variety of structurally unrelated drugs and chemicals that serve as substrates in this system.
Enzyme Induction
An interesting feature of some of these chemically dissimilar drug substrates is their ability, on repeated administration, to "induce" cytochrome P-450 by enhancing the rate of its synthesis or reducing its rate of degradation. Induction results in an acceleration of metabolism and usually in a decrease in the pharmacologic action of the inducer and also of co administered drugs. However, in the case of drugs metabolically transformed to reactive intermediates, enzyme induction may exacerbate drug-mediated tissue toxicity.
Various substrates appear to induce distinct forms of cytochrome P450 (CYP). The two isozymes that have been most extensively studied are cytochrome P4502B1 (CYP2B1), which is induced by treatment with phenobarbital; and cytochrome P45O1A1 (CYP1A1), which is induced by polycyclic aromatic hydrocarbons, of which 3-methylcholanthrene is a prototype.
Enzyme Inhibition
Environmental pollutants are capable of inducing cytochrome P-450. For example, exposure to benzo(a)pyrene, present in tobacco smoke, charcoal-broiled meat, and other organic pyrolysis products, is known to induce cytochrome P45O1A1 (CYP1A1) and to alter the rates of drug metabolism in both experimental animals and in humans.
Other environmental chemicals known to induce specific cytochrome P-450 isozymes include the polychlorinated biphenyls (PCBs), which are used widely in industry as insulating materials and plasticizers, and 2,3,7,8-tetrachlorodibenzo-p-dioxon (dioxin, TCDD), a trace by-product of the chemical synthesis of the defoliant 2,4,5-trichlorophenol and the antibacterial compound hexachlorophene.
Other drug substrates may inhibit cytochrome P-450 enzyme activity. A well-known inhibitor is proadifen (SK&F 525-A). This compound binds avidly to the cytochrome P-450 molecule and thereby competitively inhibits the metabolism of potential substrates. Cimetidine is a popular therapeutic agent that has been found to impair the in vivo metabolism of other drugs by the same mechanism.
Some substrates irreversibly inhibit cytochrome P-450 via covalent interaction of a metabolically generated reactive intermediate that may react with either the apoprotein or the heme moiety of the cytochrome. A growing list of such inhibitors includes the steroids ethinyl estradiol, norethindrone, and spironolactone; the anesthetic agent fluroxene; the antimicrobial agent chloramphenicol; the barbiturates secobarbital and allobarbital; the analgesic sedatives allylisopropylacetylurea, diethylpentenamide and ethchlorvynol; the solvent carbon disulfide; and propylthiouracil.
Parent drugs or their Phase I metabolites that contain suitable chemical groups often undergo coupling or conjugation reactions with an endogenous substance to yield drug conjugates. In general, conjugates are polar molecules that are readily excreted and often inactive. Conjugate formation involves high-energy intermediates and specific transfer enzymes. Such enzymes (transferases) may be located in microsomes or in the cytosol. They catalyze the coupling of an activated endogenous substance (such as the uridine 5'-diphosphate [UDP] derivative of glucuronic acid) with a drug (or endogenous compound), or of an activated drug (such as the S-CoA derivative of benzoic acid) with an endogenous substrate. Because the endogenous substrates originate in the diet, nutrition and disease play critical roles in the regulation of drug conjugations.
Drug conjugations were once believed to represent terminal inactivation events and as such have been viewed as "true detoxification" reactions. However, this concept must be modified, since it is now known that certain conjugation reactions (0-sulfation of N-hydroxyacetylaminofluorene and N-acetylation of isoniazid) may lead to the formation of reactive species responsible for the hepatotoxicity of the drug.
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