Drug Metabolism Lecture Notes PDF

L6 Dr. Alaa AL- Sheek Mashhad Drug metabolism (Biotransformation) Renal excretion plays a major role in terminating the biologic activity of some drugs, particularly those with low molecular weight and hydrophilic. However, many drugs do not possess...

L6 Dr. Alaa AL- Sheek Mashhad Drug metabolism (Biotransformation) Renal excretion plays a major role in terminating the biologic activity of some drugs, particularly those with low molecular weight and hydrophilic. However, many drugs do not possess such physicochemical properties. Pharmacologically active organic molecules tend to be lipophilic. They are often strongly bound to plasma proteins. Such substances are not readily excreted by the kidneys. 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 drugs are transformed to more polar and hence more readily excretable products. The metabolism play an important role in the elimination of lipid- soluble drugs by metabolic conversion to more water soluble compounds. Metabolic products (metabolites) are often less active than the parent drug and may even be inactive. 1  However, some biotransformation products have enhanced activity or toxic properties. (e.g. paracetamol metabolism produce highly toxic metabolite, but it is rapidly detoxificated ) 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., morphine) are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism before reaching the systemic circulation. This process has been called a first-pass effect. Some orally administered drugs (e.g., clonazepam) 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 used to achieve therapeutically effective blood levels. The reactions of drug metabolism are catalyzed by specific cellular enzymes. 2  At the subcellular level, these enzymes may be located in the endoplasmic reticulum, mitochondria, cytosol, lysosomes, or even the nuclear envelope or plasma membrane. The liver is the most important site of drug metabolism (mostly by cytochrome P450 (CYP450) enzyme superfamily). The drug metabolism is important as: *One of the primary mechanisms by which drugs are inactivated (like ethanol) *Some of drug activity is increased by metabolism, as in activation of prodrugs (e.g. hydrolysis of enalapril to enalaprilat). 3 *The formation of polar metabolites from a non-polar drug permits efficient urinary excretion. *Some enzymatic conversions yield active compounds with a longer half- life than the parent drug, causing delayed effects of the long-lasting metabolite as it accumulates more slowly to its steady state (e.g. diazepam has a half-life of 20–50 hours, whereas its pharmacologically active metabolite desmethyldiazepam has a plasma half-life of approximately 100 hours. 4  Phase I Reactions (Microsomal Mixed Function Oxidase System) This phase include oxidation-reduction process, catalyzed by two major microsomal enzymes: Cytochrome P450 (a hemoprotein enzyme abbreviated as CYP or P450) Cytochrome P450 isoenzymes are a group of heme-containing enzymes embedded primarily in the lipid bilayer of the endoplasmic reticulum of hepatocytes. Cytochrome P450 reductase (a flavoprotein enzyme) Phase I reactions function to convert lipophilic molecules into more polar (water soluble) molecules by introducing or unmasking a polar functional group, such as -OH or -NH2. Phase I metabolism may increase, decrease, or leave unaltered the drug's pharmacologic activity. The microsomal drug oxidations require P450, P450 reductase, NADPH (nicotinamide adenine dinucleotide phosphate), and molecular oxygen. Phase I reactions include: Oxidation , reduction, and hydrolysis reactions Examples on Oxidation Reactions: 1-Aromatic hydroxylation ………. Propranolol 2-Aliphatic hydroxylation ……...... Phenobarbital 3-Oxidative dealkylation (N- , O- , S- demethylation) 4-Deamination 5  5-Desulfuration …etc Example of Reduction Reactions: Nitro reductions ………….. chloramphenicol Example of Hydrolysis Reactions: Esterase ……………. Procaine Enzyme Induction Some drugs, on repeated administration, induce cytochrome P450 enzyme by enhancing the rate of its synthesis or reducing its rate of degradation. Induction results in an acceleration of substrate metabolism (decrease the t1/2) and usually in a decrease in the pharmacologic action of the drugs metabolized by P450. However, in the case of drugs metabolically transformed to reactive metabolites, enzyme induction may exacerbate metabolite-mediated toxicity. Example of enzyme inducers: Phenobarbital, Carbamazepine, Phenytoin, Rifampicin, Ethanol (chronic use), INH, Tobacco smoke 6 Enzyme induction can cause therapeutic failure in the followings examples Contraception with contraceptive pills, Anticoagulant control with warfarin. Also enzyme induction cause alcohol tolerance and dependence Enzyme Inhibition Certain drugs may inhibit cytochrome P450 enzyme activity and results in inhibition of substrate metabolism (increase the t1/2) and usually in an increase in the pharmacologic action of the drugs metabolized by P450. In the case of drugs metabolically transformed to reactive metabolites, enzyme inhibition may decrease metabolite-mediated toxicity. Example of enzyme inhibitors: Cimetidine, ketoconazole, Erythromycin, Quinidine, Quinolone antimicrobials, Sodium valproate 7  Phase II Reactions This phase consists of conjugation reactions. If the metabolite from Phase I metabolism is sufficiently polar, it can be excreted by the kidneys. However, many Phase I metabolites are too lipophilic to be retained in the kidney tubules. A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are most often therapeutically inactive. A notable exception is morphine-6-glucuronide, which is more potent than morphine. Drugs already possessing an -OH, -HN2, or -COOH group may enter Phase II directly and become conjugated without prior Phase I metabolism. The highly polar drug conjugates may then be excreted by the kidney or bile. Phase II reactions include:  Glucuronidation (acetaminophen)  Acetylation (Sulfonamides)  Glutathione conjugation (N-acetyl-p-benzoquinonimine)  Glycine conjugation (Salicylic acid)  Sulfate conjugation (acetaminophen)  Methylation (dopamine) 8 Metabolism of Drugs to Toxic Products: The metabolism of drugs and other foreign chemicals may not always leading to detoxification and elimination of the compound. Indeed, several compounds have been shown to be metabolically transformed to reactive intermediates that are toxic to various organs. An example is acetaminophen: Acetaminophen (4%) is metabolized by cytochrome P450 into highly toxic metabolite called N-acetyl-p-benzoquinonimine but it is deactivated rapidly by glutathione (GSH). In overdose there will be consumption of GSH and the reactive metabolite will cause sever hepatotoxicity 9 Factors affecting drug metabolism: 1-Genetic factors: Pharmacogenetic differences as in some individuals acetylation conjugation reaction is very slow in comparison to others. The defect in slow acetylators (of isoniazid and similar amines) because they synthesize less enzyme responsible for acetylation. Inherited as an autosomal recessive trait, the slow acetylators' phenotype occurs in about 50% of blacks and whites in the USA. Rapid acetylators have more hepatic acetyl N transferase enzyme than slow acetylators. 10 Ninety percent of Asians and Eskimos are rapid acetylators. Egyptians and Medetranains are slow acetylators Similarly, genetically determined defects in the oxidative metabolism (hydroxylation) of warfarin and other drugs have been reported. The defects are apparently transmitted as autosomal recessive traits. 2-Diet & Environmental Factors: Grapefruit juice is known to inhibit the P450 metabolism of co- administered drug substrates. Chargrilled food induce CYPIA enzyme. Cigarette smokers metabolize some drugs more rapidly because of enzyme induction. 3-Age: 11 *Increased susceptibility to the pharmacologic or toxic activity of drugs has been reported in very young and old patients compared with young adults slower metabolism could be due to reduced activity of metabolic enzymes or reduced availability of essential endogenous cofactors. 4- Sex *Sex-dependent variations in drug metabolism have been well documented in rats but not in human. Clinical reports suggest that similar sex-dependent differences in drug metabolism also exist in humans for ethanol, and some drugs Nicotine and aspirin seems to be metabolized more rapidly in men than women. 5-Drug-Drug Interactions during Metabolism: Administration of an enzyme inducer may enhance not only the metabolism of other drugs but also its own metabolism. Thus, continued use of some drugs may result in a pharmacokinetic type of tolerance (progressively reduced effectiveness due to enhancement of their own metabolism). Enzyme inhibition may augment plasma drug levels and lead to toxic effects from drugs with narrow therapeutic indices. Example cimetidine, a drug used for peptic ulcer, has been shown to potentiate the pharmacologic actions of anticoagulants and sedatives. 12 6-Diseases Affecting Drug Metabolism: *Chronic liver diseases (like liver cirrhosis) may significantly impair hepatic drug-metabolizing enzymes, particularly microsomal oxidases. *Cardiac disease, by limiting blood flow to the liver, may impair metabolism of drugs readily metabolized by the liver. *Pulmonary disease may also affect drug metabolism, e.g. impaired hydrolysis of procaine in patients with chronic respiratory insufficiency *Hypothyroidism increases the half-life of digoxin, whereas hyperthyroidism has the opposite effect. 13