Drug metabolism is themetabolic breakdown ofdrugs by livingorganisms, usually through specializedenzymatic systems. More generally,xenobiotic metabolism (from the Greekxenos "stranger" and biotic "related to living beings") is the set ofmetabolic pathways that modify the chemical structure ofxenobiotics, which are organic compound's that are foreign to an organism's normal biochemistry, such as anydrug,pollutant, orpoison. These pathways are a form ofbiotransformation that are present in all major groups of organisms, a fact which may allude to anancient origin. These reactions often act todetoxify poisonous compounds (although in some cases theintermediates in xenobiotic metabolism may cause toxic effects). The study of drug metabolism is one of the tenets ofpharmacokinetics (PK) as metabolism (M), the fourth stage ofLADME (a drug's transit through the body), involves the enzymatic biotransformation and non-enzymatic biotransformation of a drug, thereby leading to the fifth stage, excretion (E).[1]
The metabolism ofpharmaceutical drugs is an important aspect ofpharmacology andmedicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affectsmultidrug resistance ininfectious diseases and inchemotherapy forcancer, and the actions of some drugs assubstrates orinhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardousdrug interactions. These pathways are also important inenvironmental science, with the xenobiotic metabolism ofmicroorganisms determining whether a pollutant will be broken down duringbioremediation, orpersist in the environment. The enzymes of xenobiotic metabolism, particularly theglutathioneS-transferases are also important in agriculture, since they may produce resistance topesticides andherbicides.
Drug metabolism is divided into three phases. In phase I, enzymes such asCytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalyzed bytransferase enzymes such as glutathioneS-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognized byefflux transporters and pumped out of cells. Drug metabolism often convertslipophilic compounds intohydrophilic products that are more readilyexcreted.[2]
The exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time; these are major characteristics of xenobiotic toxic stress.[3] The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normalmetabolism. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificityenzymatic systems.
All organisms usecell membranes as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membranes, and the uptake of useful molecules is mediated throughtransport proteins that specifically select substrates from the extracellular mixture. This selective uptake means that mosthydrophilic molecules cannot enter cells, since they are not recognized by any specific transporters.[4] In contrast, the diffusion ofhydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot excludelipid-soluble xenobiotics using membrane barriers.
However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolize almost any non-polar compound.[3] Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.
The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are theglyoxalase system, which removes the reactivealdehyde methylglyoxal,[5] and the various antioxidant systems that eliminatereactive oxygen species.[6]
The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells.
In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications ishydroxylation catalyzed by thecytochrome P-450-dependent mixed-function oxidase system. These enzyme complexes act to incorporate an atom of oxygen into nonactivatedhydrocarbons, which can result in either the introduction of hydroxyl groups orN-, O- and S-dealkylation of substrates.[7] The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactiveoxyferryl species, according to the following scheme:[8]
Phase I reactions (also termed nonsynthetic reactions) may occur byoxidation,reduction,hydrolysis,cyclization, decyclization, and addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve acytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism includephenothiazines,paracetamol, and steroids. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which anendogenoussubstrate combines with the newly incorporated functional group to form a highly polar conjugate.
A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (prodrug) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one (toxification). Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions. For example, phase I metabolism convertsacetonitrile toglycolonitrile (HOCH2CN), which rapidly dissociates intoformaldehyde andhydrogen cyanide.[9]
Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts.[10] This example of abiomimetic reaction tends to give products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceuticaltrimebutine, desmethyltrimebutine (nor-trimebutine), can be efficiently produced by in vitro oxidation of the commercially available drug. Hydroxylation of anN-methyl group leads to expulsion of a molecule offormaldehyde, while oxidation of theO-methyl groups takes place to a lesser extent.
Cytochrome P450 reductase, also known as NADPH:ferrihemoprotein oxidoreductase, NADPH:hemoprotein oxidoreductase, NADPH:P450 oxidoreductase, P450 reductase, POR, CPR, CYPOR, is a membrane-bound enzyme required for electron transfer to cytochrome P450 in the microsome of the eukaryotic cell from a FAD- and FMN-containing enzyme NADPH:cytochrome P450 reductase. The general scheme of electron flow in the POR/P450 system is:NADPH→FAD→FMN→P450→O2
During reduction reactions, a chemical can enterfutile cycling, in which it gains a free-radical electron, then promptly loses it tooxygen (to form asuperoxide anion).
In subsequent phase II reactions, these activated xenobiotic metabolites areconjugated with charged species such asglutathione (GSH),sulfate,glycine, orglucuronic acid. Sites on drugs where conjugation reactions occur includecarboxy (-COOH),hydroxy (-OH),amino (NH2), andthiol (-SH) groups. Products of conjugation reactions have increased molecular weight and tend to be less active than their substrates, unlike Phase I reactions which often produceactive metabolites. The addition of large anionic groups (such as GSH) detoxifies reactiveelectrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.
These reactions are catalyzed by a large group of broad-specificity transferases, which in combination can metabolize almost any hydrophobic compound that contains nucleophilic or electrophilic groups.[3] One of the most important classes of this group is that of theglutathioneS-transferases (GSTs).
| Mechanism | Involved enzyme | Co-factor | Location | Sources |
|---|---|---|---|---|
| methylation | methyltransferase | S-adenosyl-L-methionine | liver, kidney, lung, CNS | [11] |
| sulphation | sulfotransferases | 3'-phosphoadenosine-5'-phosphosulfate | liver, kidney, intestine | [11] |
| acetylation | acetyl coenzyme A | liver, lung, spleen, gastric mucosa,RBCs, lymphocytes | [11] | |
| glucuronidation | UDP-glucuronosyltransferases | UDP-glucuronic acid | liver, kidney, intestine, lung, skin, prostate, brain | [11] |
| glutathione conjugation | glutathioneS-transferases | glutathione | liver, kidney | [11] |
| glycine conjugation | Two step process:
| glycine | liver, kidney | [12] |
After phase II reactions, the xenobiotic conjugates may be further metabolized. A common example is themercapturic acid pathway, which is the processing ofglutathione (GSH) conjugates toN-acetylcysteine (mercapturic acid) conjugates.[13][14] Here, theγ-glutamate andglycine residues in the glutathione molecule are removed bygamma-glutamyl transpeptidase anddipeptidases. In the final step, thecysteine residue in the conjugate isacetylated.
Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of themultidrug resistance protein (MRP) family.[15] These proteins are members of the family ofATP-binding cassette transporters and can catalyze the ATP-dependent transport of a huge variety ofhydrophobic anions,[16] and thus act to remove phase II products to the extracellular medium, where they may be further metabolized or excreted.[17]
The detoxification of endogenous reactive metabolites such asperoxides and reactivealdehydes often cannot be achieved by the system described above. This is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are theglyoxalase system, which acts to dispose of the reactive aldehydemethylglyoxal, and the variousantioxidant systems that removereactive oxygen species.
Quantitatively, thesmooth endoplasmic reticulum of theliver cell is the principal organ of drug metabolism, although everybiological tissue has some ability to metabolize drugs. Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in thegut, and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is taken into the GI tract, where it enters hepatic circulation through theportal vein, it becomes well-metabolized and is said to show thefirst pass effect.
Other sites of drug metabolism includeepithelial cells of thegastrointestinal tract,lungs,kidneys, and theskin.These sites are usually responsible for localized toxicity reactions.
The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. TheCytochrome P450 monooxygenase system (CYP) is a crucial pathway in this regard. In general, anything thatincreases the rate of metabolism (e.g.,enzyme induction) of a pharmacologically active metabolite willdecrease the duration and intensity of the drug action. The opposite is also true, as inenzyme inhibition. However, in cases where an enzyme is responsible for metabolizing a pro-drug into a drug, enzyme induction can accelerate this conversion and increase drug levels, potentially causing toxicity.[medical citation needed] For example, chemotherapy prodrugs likecyclophosphamide (CPA) andifosfamide (Ifex), which are initially inactive, become toxic as they are metabolized intocytotoxic compounds (such asphosphoramide mustard andchloroacetaldehyde) primarily from liver enzymesCYP2B6[18] andCYP3A4.Co-administration of a strong CYP inducer, such asphenytoin orrifampicin, accelerates metabolism and increases the rate ofbioactivation which causes a higher concentration of cytotoxic metabolites that may lead to higher toxicity. This drug–drug interaction may enhance the risk of adverse effects, most notably severemyelosuppression andhemorrhagic cystitis.[19][20][21]
Typically,drug-drug interactions are formally quantified by comparing the observed combined effect of two co-administered drugs against a theoretical baseline of no interaction. This concept, commonly referred to as theadditive effect, explains the synergistic interaction, or lack thereof, between drugs. In order to validly quantify the effect, two primary null models are used: loewe additivity and bliss independence.[22]Loewe additivity (dosage additivity) postulates that if two drugs share the same mechanism of action, their combined effects should be identical to the effect achieved from taking a higher dose of either drug alone.[23] Bliss independence (response additivity) postulates that if two drugs act independently of each other, their combined effect should be the product of their individual effects. Both models identify two combined effects that signal a true drug interaction, as they deviate from the additive baseline: a synergistic effect, where the observed combined effect is greater than predicted which results in higher efficacy or toxicity levels; and an antagonistic effect, where the observed combined effect is less than predicted which often results indrug therapy problems.[23][24]
The therapeutic index (TI) of a drug is the measurement of its efficacy, calculated as the ratio of the median toxic dose (TD50) to the median effective dose (ED50).[25] Various Cytochrome P450 metabolic enzymes are inhibited or induced by many drugs. For example, chronic alcohol consumption will induce Cytochrome P450 enzymes, likeCYP2E1, which enhances the metabolism of ethanol.[26] As a consequence, the induction of CYP2E1 will increase a person's tolerance levels and reduce the toxicity of ethanol. Additionally, CYP2E1 is involved with the metabolism of acetaldehyde (CH₃CHO), a metabolite of alcohol that is highly reactive and toxic, which can contribute to an alcohol-induced liver injury along withoveroxidation.[27]
Variousphysiological andpathological factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g.,pharmacogenetics),enterohepatic circulation,nutrition,sex differences orgut microbiota.[28] This last factor has significance because gut microorganisms are able to chemically modify the structure of drugs through degradation and biotransformation processes, thus altering the activity and toxicity of drugs. These processes can decrease the efficacy of drugs, as is the case ofdigoxin in the presence ofEggerthella lenta (E. lenta) in themicrobiota.[29] Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs.[29] An example of polymorphism affecting drug metabolism is the alcohol flush reaction caused by the ALDH2 genetic mutation. The ALDH2 genetic mutation is prevalent among east Asians and causes a reduced activity of aldehyde dehydrogenase (ALDH), which assists in breaking down acetaldehyde (CH₃CHO).[30] As of 2019, approximately 560 million people (8% of the world's population in 2019) had this genetic mutation, which posed various health risks like metabolic disorders or an increased cancer risk.[31]
In general, drugs are metabolized more slowly infetal,neonatal andelderlyhumans andanimals than inadults. Inherited genetic variations in drug-metabolizing enzymes result in different catalytic activity levels. For example,N-acetyltransferases (involved inPhase II reactions), individual variation creates a group of people who acetylate slowly (slow acetylators) and those who acetylate quickly (rapid acetylators), split roughly 50:50 in the population of Canada. However, variability inNAT2 alleles distribution across different populations is high, and some ethnicities have a higher proportion of slow acetylators.[32] This variation in metabolizing capacity may have dramatic consequences, as theslow acetylators are more prone to dose-dependent toxicity.NAT2 enzyme is a primary metabolizer of antituberculosis (isoniazid), some antihypertensive (hydralazine), anti-arrhythmic drugs (procainamide), antidepressants (phenelzine) and many more[33] and increased toxicity as well as drug adverse reactions in slow acetylators have been widely reported. Similar phenomena of altered metabolism due to inherited variations have been described for other drug-metabolizing enzymes, likeCYP2D6,CYP3A4,DPYD,UGT1A1.DPYD andUGT1A1 genotyping is now required before administration of the corresponding substrate compounds (5-FU andcapecitabine for DPYD andirinotecan for UGT1A1) to determine the activity of DPYD and UGT1A1 enzyme and reduce the dose of the drug in order to avoid severe adverse reactions.[34]
Dose, frequency, route of administration, tissue distribution, and protein binding of the drug affect its metabolism.[35]Pathological factors can also influence drug metabolism, includingliver,kidney, orheart disease.[36][37][38]
In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects.[39] This can be used to identify individuals most at risk from adverse reaction.
Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such asbenzaldehyde could be oxidized and conjugated to amino acids in the human body.[40] During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such asmethylation,acetylation, andsulfonation.
In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication byRichard Williams of the bookDetoxication mechanisms in 1947.[41] This modern biochemical research resulted in the identification of glutathioneS-transferases in 1961,[42] followed by the discovery of cytochrome P450s in 1962,[43] and the realization of their central role in xenobiotic metabolism in 1963.[44][45]
Glycine conjugation of mitochondrial acyl-CoAs, catalyzed by glycine N-acyltransferase (GLYAT, E.C. 2.3.1.13), is an important metabolic pathway responsible for maintaining adequate levels of free coenzyme A (CoASH). However, because of the small number of pharmaceutical drugs that are conjugated to glycine, the pathway has not yet been characterized in detail. Here, we review the causes and possible consequences of interindividual variation in the glycine conjugation pathway. ...
Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
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