Pharmacokinetics - Drug metabolism / biotransformation

Pharmacokinetics - Drug metabolism / biotransformation

            Drugs and other foreign chemicals (collectively called as Xenobiotics) may be present in two forms in animal’s body: 1. Polar, water soluble compounds that usually are not metabolized to any appreciable extent & are excreted unchanged, 2. Non-polar, lipid soluble compounds that first must be metabolically transformed to more polar & water soluble forms that only then can be efficiently excreted in urine / bile.

            Elimination of drugs refers to all processes that operate to reduce the concentration of the drug in the body fluids. Hepatic metabolism and renal excretion are the principal mechanisms of drug elimination.

Metabolism is the term used to denote normal anabolic and catabolic reactions of the body. Biotransformation is probably the best term useful for describing the biological fate of foreign compounds.

Humans and animals are exposed to a wide variety of xenobiotics. Exposure to environmental xenobiotics may be inadvertent and accidental and may be inescapable. Some xenobiotics are innocuous, but many can provoke biologic responses that are both pharmacologic and toxic in nature. These biologic responses often depend on conversion of the absorbed substance into active metabolite.

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. Most drugs do not possess such physicochemcial properties. 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 by the glomerulus. The lipophilic nature of renal tubular membranes also facilitates the re-absorption 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 into more polar and hence more readily excretable products.

The role metabolism may play in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates may have half-life greater than 100 years if it were not for their metabolic conversion to more water-soluble compounds.

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, teratogenicity and carcinogenicity. This observation undermines one popular theory that biotransformation is a biochemical defense mechanism for the detoxification of environmental xenobiotics. Sometimes lethal substances are synthesized due to biotranformation and this is known as lethal synthesis.

Some drugs are pharmacologically inactive until they are metabolized and such drugs are known as pro-drugs. In some cases both the drug and its metabolite may be active.

There are several possible consequences of the biochemical transformation of drugs.

They are

1.  Inactivation, during which an active drug is converted to an inactive metabolite

E.g.:     Amphetamine to Para-OH-amphetamine

            Phenothiazine to Phenothiazine sulphoxide

2. Activation, during which an inactive drug (pro-drug) is converted to a pharmacologically active primary metabolite

E.g.:     Prontosil to Sulphonamide

            Hexamine to Formaldehyde

            Chloral hydrate to Trichloroethanol

3. Modification of the activity following conversion of an active drug to a metabolite that also possesses pharmacological activity

E.g.:     Aspirin to Salicylic acid

            Phenylbutazone to Oxyphenbutazone

            Propranolol to 4 – OH propranolol

4. Conjugation (detoxification) through which a molecule that is usually much more polar is attached to the parent compound or to its metabolite with a marked increase in water solubility and a complete loss of pharmacological activity

5. Lethal synthesis in which a drug is incorporated into a normal cellular metabolic pathway that ultimately leads to failure of the reaction sequence because of the presence of spurious substrates.

E.g.:     Parathion to Paraoxon

            Malathion to Maloxon

            Methanol to Formaldehyde to Formic acid

            Flurocitrate to Fluoroacetate

Role of biotransformation in drug disposition

Most metabolic biotransformations occur at some point between absorption of drug into the general circulation and its renal elimination. Although the liver is the most active site for biotransformations, a few transformations occur in the intestinal lumen (bacterial activity) or intestinal wall (villi). In general all of these reactions are grouped into two major categories as Phase I and Phase II reactions.

ABSORPTION	METABOLISM		ELIMINATION
Drug	Phase I Drug metabolite with modified activity Inactive Drug metabolite	Phase II Conjugate  Conjugate
Lipophilic			Hydrophilic

Phase I reactions are asynthetic / non synthetic reactions that usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group. Often these metabolites are inactive, although in some instances activity is only modified. If Phase I metabolites are sufficiently polar, they may be excreted. However, many Phase I products are not eliminated and undergo a subsequent reaction, in which endogenous substrates combine with the newly formed functional group to form a highly polar conjugate. A great variety of drugs undergo these sequential biotransformation reactions. Although in some instances the parent drug may already possess a functional group that may form a conjugate directly. This conjugate may form a substrate for the Phase I reaction.

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 are absorbed intact from the small intestine and transported via the portal system to the liver, where they undergo extensive metabolism. This process is called first-pass effect / Pre systemic metabolism. Some orally administered drugs are more extensively metabolized in the intestine than the liver. Thus intestinal metabolism may contribute to the first-pass effect. First-pass effect may greatly limit the bioavailability of orally administered drugs. The lower gut harbours 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., insulin) or by enzymes in the wall of the intestine (e.g., sympathomimetic catecholamines).

Although drug biotransformation in vivo can occur by spontaneous, noncatalysed chemical reactions, the vast majority are catalysed 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.

Phase I Reactions

1. Oxidation: Addition of O₂ / removal of hydrogen. It is the most frequently occurring reaction. Most oxidation reactions involve initial hydroxylation. There are three types of oxidation:

a. Microsomal Oxidation: These reactions are catalyzed by microsomal enzyme system and are called as microsomal oxidation. It is the most predominant biotransformation reaction for lipid soluble and steroid drugs. 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, they re-form into vesicles called microsomes. The rough microsomes tend to be dedicated to protein synthesis and the smooth microsomes are relatively rich in enzymes responsible for oxidative drug metabolism. They contain the important class of enzymes known as the Mixed Function Oxidases or monooxygenases. Microsomal oxidation requires cytochrome P-450, cytochrome P-450 reductase, NADPH and molecular oxygen.

NADPH + A + H⁺ ------à AH₂ + NADP⁺

AH₂ + O₂ -----------------à Active oxygen complex

Active oxygen complex + Drug --à Oxidised drug + A +H₂O

A represents oxidised form of Cytochrome P 450 and AH₂  represents reduced form .

Oxidized Fe3+ cytochrome P450 combines with a drug substrate to form a binary complex. NADPH donates an electron to the flavoprotein reductase, which in turn reduces the oxidized cytochrome P450 drug complex. A second electron is introduced from NADPH via the same flavoprotein reductase, which serves to reduce molecular oxygen and to form an "activated oxygen" - cytochrome P450 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 permits 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 Some drugs have the ability on repeated administration to "induce" cytochrome P-450 by enhancing its rate of synthesis or by 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 coadministered drugs. However, in the case of drugs metabolically transformed to reactive intermediates, enzyme induction may exacerbate drug-mediated tissue toxicity. Some drugs that act as inducers are griseofulvin, phenobarbital, phenylbutazone, phenytoin and rifampin.

Enzyme inhibition Some drugs have the ability on repeated administration to "inhibit" cytochrome P-450 enzyme activity. These drugs cause a reduction in the metabolism of other drugs that are administered subsequently. Some drugs that act as inhibitors are chloramphenicol, cimetidine, dicumarol, oral contraceptives, ethanol and isoniazid.

            b. Non microsdomal oxidation / Mitochondrial oxidation: MAO (Mono Amine Oxidase) is the mitochondrial enzyme located in the outer membrane of the mitochondria and is widely distributed in variety of tissues like liver, spleen, heat muscle, neuron, lungs, kidney, intestinal mucosa, etc. MAO generally deaminate biogenic amines.

            c. cytoplasmic oxidation: alcohols are oxidized to aldehydes and aldehydes are oxidized to acids by dehydrogenase enzymes.

            Oxidation reactions: N-dealkylation, Desulfuration, O-dealkylation, Deamination, N-oxidation, Aromatic hydroxylation, Sulfoxide formation, Aliphatic hydroxylation, Epoxidation, Monoamine oxidation, Alcohol/aldehyde dehydrogenation.

            Reactions                                                         Examples

a. N- and O- dealkylation                                    Phenacetin, morphine, codeine, diazepam

b. Aliphatic and aromatic hydroxylation              Phenobarbital, Phenytoin, Phenylbutazone

c. N-Oxidation                                                   Guanethidine, Acetaminophen, Nicotine

d. Sulphoxide formation                                                Chlorpromazine

e. Deamination of amine                                    Amphetamine

f. Desulfuration                                                 Thiobarbitol, parathion

            2. Reduction: Addition of H⁺ / removal of O₂. Microsomal reduction occurs less frequently than microsomal oxidation. Many Halogenated compounds and nitrated aromatic compounds are reduced by microsomal enzymes.

 

Reactions                                                         Examples

a. Azo reduction                                                Prontosil

b. Nitro reduction                                              Chloramphenicol

            3. Hydrolysis: Hydrolytic clevage reactions can take place in the plasma / in tissues and are applicable to drugs having ester and amide groups.

            Reactions                                             Examples

Hydrolysis of esters and amides                                    Procaine

            They result in either activation / inactivation of drugs. The rate of hydrolysis of amides are generally slower than esters.

Phase II Reactions:

            These Phase II reactions may actually precede Phase I reactions. They usually result in drug inactivation. A drug can be a substrate for more than one enzyme and for this reason many give rise to several metabolites each of which can undergo further reaction. These reactions may take place when a drug / Phase – I metabolite contain a chemical group such as

-OH, -COOH, -SH, -NH groups and is suitable for combining with endogenous compounds provided by the body to form readily excreted water soluble polar metabolites.

Conjugating agents: Glucuronic acid, Glycine, Cysteine, Methionine, Sulfates, Acetyl groups, etc.

            A conjugation reaction requires the following: 1. Conjugating agent, 2. Nucleotide,

3. Transferring enzyme.

            Such enzymes (transferases) may be located in microsomes or in the cytosol. They catalyze the coupling of an activated endogenous substance or of an activated drug with an endogenous substance. Because the endogenous substrates originate in the diet, nutrition and disease (resulting in inanition) play critical roles in the regulation of drug conjugations.

            Drug conjugates 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 may lead to the formation of reactive species responsible for the hepatotoxicity of the drug.

            a. Glucuronide conjugation: It is the most important pathway for drugs and certain endogenous substances like steroid hormones, thyroxine and bilirubin. Glucuronides are mainly synthesized by liver, but also occur in kidney and tissues to a lesser extent. Glucuronic acid is derived from glucose and the transferring enzyme is Glucuronyl transferase. E.g.: Morphine, Salicylate, Acetaminophen, Digitoxin, Chloramphenicol and Phase I metabolites of Diazepam, phenylbutazone, phenobarbitol and Phenytoin.

            Glucuronides are more water soluble and are more suitable for carrier mediated excretion in to urine and bile. Glucuronyl conjugates may be extensively excreted in bile, the degree of which appears to be determined largely by molecular weight. This route of elimination may predominate for compounds with molecular weights above 500 and is relatively more common in rats, dogs, and chickens than in other species. Glucuronides that are excreted in bile may undergo hydrolysis in intestine. The hydrolytic reaction liberates the drug or phase I metabolite, which may then be reabsorbed, and an Enterohepatic cycle may be established.

Felines are deficient in glucuronyl transferase. Defective synthesis of glucuronides in cats is related to the low level of the transferring enzyme rather thana defieciency of UDPGA (the activated form of glucuronic acid is the nucleotide Uridine diphosphate glucuronic acid). Certain breeds of fish do not synthesise glucuronides, which is apparently due to deficiency of UDPGA. In insects, glucuronide formation is replaced by β-glucoside conjugation.

            b. Sulfate conjugation: It is an important alternate pathway to the first one. It occurs with phenols and aliphatic alcohols. Since the total pool of sulphate in the body canbe readily exhausted, the conjugation with glucuronides are usually predominant over sulphate formation. E.g.: Phenol, acetaminiphen, ascorbic acid, morphine, isoproterenol, various endogenous compounds such as chondroitin, heparin, and certain steroids. Enzymes that catalyze formation of the nucleotide and transfer of the conjugating agent to the acceptor molecule are found in the soluble fraction of the liver.

            Capacity for sulfate conjugation in the pig is limited and hence can be saturated, yielding a change from a constant fraction of drug metabolized (first order) to a constant amount of drug metabolized (zero order).

            c. Acetylation: This reaction occurs for all aminoacids in many species, except dog and fox. Dogs don’t acetylate the aromatic amino groups as it lacks the specific enzyme. Acetylation is the principal metabolic pathway for sulphonamide compounds in humans, rabbits, and rats but is accompanied by aromatic hydroxylation in ruminant species.

            The acetylation reaction takes place in two stages: first step involves formation of acetyl coenzyme A and is followed by a nucleophillic attack by the amino containing compound on the acetylated enzyme. This reaction takes place in the reticuloendothelial rather than parenchymal cells of liver, spleen, lungs, and intestinal mucosa.

            Acetylation decreases water solubility as well as lipid solubility of sulphonamide compounds, except sulfapyrimidine, sulfadoxine and sulfadimethoxine.

Transacetylases maybe more specific for the type of amino group.

Other Phase II reactions:

            Sulfhydryl containing drugs and/or phase I metabolites are subject to conjugation with other molecules containing free –SH groups. These may be either endogenous compounds or xenobiotics.

Reaction                                               Example

Conjugation with glycine                                    Salicylic acid, Nicotinic acid

Conjugation with sulphate                                  Steroids

O-, S-, and N- methylation                                  Norepinephrine, Histamine,

Glutathione conjugation                         Ethacrynic acid

            Metabolic transformations mediated by GI Microorganisms

            GI microflora are capable of mediating a wide variety of metabolic transformations, the most prominent of which are hydrolytic and reductive reactions. Microbial metabolism may occur after oral administration of a drug product or following passive diffusion of the nonionized form of a drug from the systemic circulation to the lumen of the GIT. Enteric sulphonamides depend on release of sulfathiazole for their antibacterial action (e.g., phthalylsulfathiazole, succinylsulfathiazole).  Hydrolysis mediated by bacterial enzymes in the large intestine is also responsible for activation of the anthraquinone glycosides (cascara sagrada, senna). Hydrolysis of glucuronide conjugates that are excreted in bile underliesthe phenomenon of Enterohepatic circulation, since only the drug itself is lipid-soluble and can be reabsorbed. The enzyme responsible for this hydrolytic reaction, β-glucuronidase, is found principally in bacteria (E.coli) of the large intestine. Both azo- and nitro- reductase activity are also associated with gut flora.

            Ruminal microflora catalyze hydrolytic and reductive reactions: e.g., Cardiac glycosides are hydrolyzed in the rumen, and Chloramphenicol is inactivated by reduction of the nitro group. Parathion, which is the precursor of the active pesticide paraon, may undergo nitroreduction in the rumen. This metabolic reaction reduces both the activity and toxicity of the irreversible anticholinesterase agent.

            Chronic administration of antimicrobial agents can adversely affect activity of these bacteria. Since, they are located mainly in the large intestine and rumen, microflora may be exposed to action an antimicrobial agent irrespective of the route of administration. The extent of bacterial exposure to a drug depends on the extent of absorption from the small intestine and, following parenteral administration, the amount of drug that is excreted into the large intestine and rumen. These translocation processes are determined by the lipid solubility and degree of ionization of the drug.

Clinical relevance of drug biotransformation

The dose and the frequency of administration required to achieve effective therapeutic blood and tissue levels vary in different patients because of individual differences in drug distribution and rates of drug metabolism and excretion. These differences are determined by genetic factors and nongenetic variables such as age, sex, liver function, circadian rhythm, body temperature and nutritional and environmental factors such as concomitant exposure to inducers or inhibitors of drug metabolism. Some factors affecting drug metabolism include

1.   Species differences - A drug that is safe for use in one species may produce severe side effects in another. Certain drugs must be used cautiously or not at all in cats to avoid toxic and potentially lethal side effects. One of the most important conjugation pathways in mammals involves combining a molecule of Phase I drug metabolite with a molecule of glucuronic acid. A cat's ability to synthesize the glucuronic acid is deficient in contrast to most other animals. Thus drugs that are normally metabolized using this conjugation pathway are shunted to other, less efficient metabolic pathways, requiring more time for the drug to be metabolized and subsequently eliminated. Salicylate compounds like aspirin are normally conjugated with glucuronic acid, but they are also excreted unchanged in the urine. Even though one of the major metabolic pathways for aspirin like compounds is deficient in cats, they can still tolerate careful use of these drugs. Dogs lack the ability to acetylate aromatic amino groups such as those present in sulphonamides. Ruminants have low plasma pseudocholinesterease levels; therefore drugs such as succinylcholine have a longer duration of action in ruminants than in horses, dogs and cats.

2.   Age – Hepatic drug metabolism generally increases from birth, to reach a maximum when the animal is a young adult. As animals age thereafter, metabolism reduces gradually, with the rate of decrease in biotransformation efficiency increasing as the animal approaches geriatric age. These generalities are fraught with exceptions, and specific situations must be addressed.

            In ruminants, clear changes in metabolism result when preruminant animal become ruminants. Cytochrome P-450 and NADPH-dependent reductases increase by 50%; analine hydroxylase increases by three fold; and ethoxycoumarin O-deethylase, UDP glucuronic acid glucuronyl transferase, and glutathione S-transferase all are increased subsequent to the development of a functional rumen. Such maturational changes, likely because of the increased complexity of the nutrients being exposed to the liver as a result of the dietary change, is consistent with the quantum increase in the rate of elimination of ceftiofur and desfuroylceftiofur-related metabolites in ruminant cattle compared with preruminant cattle.

Newborn and very young animals tend to be less tolerant to certain drugs than mature animals. Drugs that are normally oxidized, reduced or conjugated with glucuronic acid as part of their biotransformation and excretion accumulate more readily in a young animals’ liver because these metabolic pathways are more limited than in the adult liver, resulting in a slow elimination of drugs.

3.   Individual differences - Individual differences in the rate of metabolism depend on the nature of the drug itself. Genetic and environmental factors also contribute to individual variations in drug metabolism. Cigarette smokers metabolize some drugs more rapidly than nonsmokers because of enzyme induction. Industrial workers exposed to some pesticides metabolize certain drugs more rapidly than nonexposed individuals. Such differences make it difficult to determine effective and safe doses of drugs that have narrow therapeutic indices.

4.   Sex - Sex dependent variations in drug metabolism have been well documented in rats but not in other rodents. Young adult male rats metabolise drugs much faster than mature female rats or prepubertal male rats. These differences have been clearly associated with androgenic hormones. A few clinical reports suggest that similar sex-dependent differences in drug metabolism also exist in other animals for benzodiazepines, oestrogens and salicylates.

5.   Drug-drug interactions during metabolism - Many substrates, by virtue of their relatively high lipophilicity, are retained not only at the active site of the enzyme but also remain nonspecifically bound to the lipid membrane of the endoplasmic reticulum. In this state, they may induce microsomal enzymes; depending on the residual drug levels at the active site, they also may competitively inhibit metabolism of a simultaneously administered drug. Such drugs include various sedative-hypnotics, tranquilizers, anticonvulsants and insecticides. Patients given routine barbiturate therapy, other sedative-hypnotics or tranquilizers may require considerable higher doses of warfarin or dicumarol when being treated with these oral anticoagulants to maintain prolonged prothrombin time. On the other hand, discontinuation of sedative may result in reduced metabolism of the anticoagulant and bleeding - a toxic effect on the enhanced plasma levels of the anticoagulant. Similar interactions have been observed in individuals receiving various drug regimens such as tranquilizers or sedatives with contraceptive agents, sedatives with anticonvulsant drugs and even alcohol and hypoglycemic drugs. It must also be noted that an induced may enhance not only the metabolism of other drugs but also its own metabolism. Thus continued use of a drug may result in one form of tolerance - progressively reduced effectiveness due to enhancement of its own metabolism. Conversely, simultaneous administration of two or more drugs may result in impaired elimination of the more slowly metabolized drug and prolongation or potentiation of its pharmacologic effects. Both competitive substrate inhibition and irreversible substrate mediated enzyme inactivation may augment plasma drug levels and lead to toxic effects from drugs with narrow therapeutic indices. For example, it has been shown that dicumarol inhibits the metabolism of the anticonvulsant phenytoin and leads to the expression of side effects such as ataxia and drowsiness. Similarly, allopurinol both prolongs the duration and enhances the chemotherapeutic actions of mercaptopurine by competitive inhibition of xanthine oxidase. Consequentiy, to avoid bone marrow toxicity, the dose of mercaptopurine is usually reduced in patients receiving allopurinol. Cimetidine, a drug used in the treatment of peptic ulcer, has been shown to potentiate the pharmacologic actions of anticoagulants and sedatives. The metabolism of chlordiazepoxide has been shown to be inhibited by about 63 per cent after a single dose of cimetidine; such effects being reversed within 48 hours after the withdrawal of cimetidine. For such interactions to occur, drug metabolism must follow zero-order kinetics. Elimination of most drugs proceeds by first order kinetics, thus greatly reducing the possibility of such metabolically dependent interactions. Impairment of metabolism may also result if a simultaneously administered drug irreversibly inactivates a common metabolizing enzyme, as in the case with secobarbital or novonal overdoses. These compounds in the course of their metabolism by cytochrome P450 inactivate the enzyme and result in impairment of their own metabolism and that of the other cosubstrates.

6.   Interactions between drugs and endogenous compounds - Various drugs require conjugation with endogenous substrates such as glutathione, glucuronic acid, and sulfuric acid for their inactivation. Consequently, different drugs may compete for the same endogenous substrate, and the faster-reacting drug may effectively deplete the endogenous substrate levels and impair the metabolism of the slower reacting drug. If the latter has a steep dose response curve or a narrow margin of safety, potentiation of its pharmacologic and toxic effects may result.

6.   Diseases affecting drug metabolism

a.   Liver diseases and toxicity - Acute and chronic diseases that affect liver architecture or function markedly affect hepatic metabolism of some drugs. Such conditions include fat accumulation, alcoholic hepatitis, active or inactive alcoholic cirrhosis, hemochromatosis, chronic active hepatitis, biliary cirrhosis and acute viral or drug hepatitis. Depending on their severity, these conditions impair hepatic drug metabolizing enzymes, particularly microsomal oxidases and thereby affect drug elimination. Impairment of enzyme activity or defective formation of enzymes associated with heavy metal poisoning or porphyria also results in reduction of hepatic drug metabolism. For example lead poisoning has been shown to increase the half life of antipyrine in humans. Severe hypoproteinemia, avitaminosis B or energy deficiency may also lead to a depletion of hepatic glycogen and to exaggerated drug response due to a functional impairment of microsomal enzyme activity.

b.   Cardiac disease - Cardiac disease by limiting the blood flow to the liver, may impair disposition of those drugs whose metabolism is flow limited. These drugs are so readily metabolized by the liver that hepatic cleareance is essentially equal to liver blood flow.

c.   Pulmonary disease - Pulmonary disease may affect drug metabolism as indicated by the impaired hydrolysis of procainamide and procaine in patients with chronic respiratory insufficiency and the increased half life of anipyrine in patients with lung cancer.

d.   Endocrine dysfunction - The effects of endocrine dysfunction have been explored in experimental animal models, corresponding clinical data for animals with endocrine disorders are scanty.

Metabolism of drugs to toxic products

It is becoming increasingly evident that metabolism of drugs and other foreign chemicals may not always be an innocuous biochemical event 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. Such toxic reactions may not be apparent at low levels of exposure to parent compounds when alternative detoxification mechanisms are not yet overwhelmed or compromised and the availability of endogenous detoxifying cosubstrates is not limited. However, when these resources are exhausted, the toxic pathway may prevail resulting in overt organ toxicity or carcinogenesis. Acetaminophen can be quoted as a typical example of this. This analgesic drug is quite safe in therapeutic doses. It normally undergoes glucuronidation and sulfation to the corresponding conjugates, which together comprise 95% of the total excreted metabolites. The alternative cytochrome P-450 dependent glutathione conjugation pathway accounts for the remaining 5%. When acetaminophen administration far exceeds the therapeutic dose the glucuronidation and sulfation pathways are saturated and the cytochrome P-450 dependent pathway becomes increasingly important. Little or no hepatotoxicity results as long as glutathione is available for conjugation. However, with time, hepatic glutathione is depleted faster than it can be regenerated and accumulation of a reactive and toxic metabolite occurs. In the absence of intracellular nucleophiles such as glutathione, this reactive metabolite reacts with nucleophilic group present on the cellular macromolecules such as protein, resulting in hepatotoxicity. The absence of a glucuronidation pathway for xenobiotics in the cat accounts for the extreme toxicity of acetaminophen to the cat. The chemical and toxicologic characterization of the electrophilic nature of the reactive acetaminophen metabolite has lead to the development of effective antidotes - cysteamine and acetylcysteine. Administration of acetylcysteine within 24 hours following acetaminophen overdosage has been shown to protect victims from fulminant hepatotoxicity and death.