Drug metabolism 1173475 220987480 2008-06-22T15:07:51Z DOI bot 6652755 Citation maintenance. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. '''Drug metabolism''' is the [[metabolism]] of [[Medication|drugs]], their [[biochemical]] modification or degradation, usually through specialized [[Enzyme|enzymatic]] systems. This is a form of [[xenobiotic metabolism]]. Drug metabolism often converts [[Hydrophobic|lipophilic]] [[chemical compound]]s into more readily [[Excretion|excreted]] [[Hydrophilicity|polar]] products. Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs. [[Medication|Drug]] metabolism can result in [[toxication]] or [[detoxication]] - the activation or deactivation of the chemical. While both occur, the major metabolites of most drugs are detoxication products. Drugs are almost all [[xenobiotic]]s. Other commonly used [[organic chemical]]s are also xenobiotics, and are metabolized by the same [[enzyme]]s as drugs. This provides the opportunity for ''[[drug-drug interaction|drug-drug]]'' and ''[[drug-chemical interaction|drug-chemical]]'' [[drug interaction|interactions]] or reactions. == Phase I vs. Phase II == '''Phase I''' and '''Phase II''' reactions are [[biotransformation]]s of chemicals that occur during drug metabolism. ''Phase I reactions'' usually precedes Phase II, though not necessarily. During these reactions, polar bodies are either introduced or unmasked, which results in (more) polar metabolites of the original chemicals. In the case of pharmaceutical drugs, Phase I reactions can lead either to activation or inactivation of the drug. Phase I reactions (also termed nonsynthetic reactions) may occur by [[oxidation]], [[Redox|reduction]], [[hydrolysis]], cyclization, and decyclization reactions. Oxidation involves the enzymatic addition of oxygen or removal of hydrogen, carried out by mixed function oxidases, often in the liver. These oxidative reactions typically involve a [[Cytochrome P450 oxidase|cytochrome P450]] haemoprotein, NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines, [[Paracetamol#Metabolism|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 an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate. ''Phase II reactions'' — usually known as conjugation reactions (e.g., with [[glucuronic acid]], [[sulfonates]] (commonly known as sulfation) , [[glutathione]] or [[amino acids]]) — are usually [[detoxication]] in nature, and involve the interactions of the polar functional groups of phase I metabolites. == Sites == Quantitatively, the [[smooth endoplasmic reticulum]] of the [[liver]] cell is the principal organ of drug metabolism, although every [[biological 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 the [[gut]], 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 the portal vein, it becomes well-metabolized and is said to show the ''[[first pass effect]]''. Other sites of drug metabolism include [[epithelial cell]]s of the [[gastrointestinal tract]], [[lung]]s, [[kidney]]s, and the [[skin]]. These sites are usually responsible for localized toxicity reactions. == Major enzymes and pathways == Several major enzymes and pathways are involved in drug metabolism, and can be divided into Phase I and Phase II reactions: === Phase I === ==== Oxidation ==== * [[Cytochrome P450 oxidase|Cytochrome P450 monooxygenase system]] * [[Flavin-containing monooxygenase system]] * [[Alcohol dehydrogenase]] and [[aldehyde dehydrogenase]] * [[Monoamine oxidase]] * Co-oxidation by [[peroxidase]]s ==== Reduction ==== * [[NADPH-cytochrome P450 reductase]] * [[Reduced cytochrome P450|Reduced (ferrous) cytochrome P450]] It should be noted that during reduction reactions, a chemical can enter ''futile cycling'', in which it gains a free-radical electron, then promptly loses it to [[oxygen]] (to form a [[superoxide anion]]). ==== Hydrolysis ==== * [[Esterase]]s and [[amidases]] * [[Epoxide hydrolase]] === Phase II === * [[Glutathione S-transferase]]s ** [[Mercapturic acid biosynthesis]] * [[UDP-glucuronosyltransferase]]s * [[N-acetyltransferase]]s * [[Amino acid N-acyl transferase]]s * [[Sulfotransferase]]s == Factors that affect drug metabolism == The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The [[Cytochrome P450 monooxygenase system]] is the most important pathway in this regard. In general, anything that ''increases'' the rate of metabolism (''e.g.'', [[Enzyme induction and inhibition|enzyme induction]]) of a pharmacologically active metabolite will ''decrease'' the duration and intensity of the drug action. The opposite is also true (''e.g.'', [[Enzyme induction and inhibition|enzyme inhibition]]). Various ''physiological'' and ''pathological'' factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (''e.g.'', [[pharmacogenetics]]), [[enterohepatic circulation]], [[nutrition]], [[intestinal flora]], or [[sex difference]]s. In general, drugs are metabolized more slowly in [[fetal]], [[neonatal]] and [[elderly]] [[human]]s and [[animal]]s than in [[adult]]s. Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs. With N-acetyltransferases (involved in ''Phase II'' reactions), individual variation creates a group of people who acetylate slowly (''slow acetylators'') and those who acetylate quickly, split roughly 50:50 in the population of [[Canada]]. This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity. [[Cytochrome P450 monooxygenase system]] enzymes can also vary across individuals, with deficiencies occurring in 1 - 30% of people, depending on their ethnic background. ''Pathological factors'' can also influence drug metabolism, including [[liver]], [[kidney]], or [[heart]] diseases. ''In silico'' modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects.<ref>{{cite journal | author = Amin Rostami-Hodjegan; Geoffrey Tucker | year = 2007 | title = Simulation and prediction of ''in vivo'' drug metabolism in human populations from ''in vitro'' data | journal = Nature Reviews Drug Discovery | volume = 6 | issue = 2 | pages = 140–148| url = http://www.ncbi.nlm.nih.gov/pubmed/17268485?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum | doi = 10.1038/nrd2173 }}</ref>. This can be used to identify individuals most at risk from adverse reaction. == See also == * [[Active metabolite]] * [[Simcyp Simulator]] == External links == * [http://umbbd.msi.umn.edu/ University of Minnesota Biocatalysis/Biodegradation Database] * [http://www.drugmetabolism.co.uk/ReactionSelector2.aspx Drug Metabolism Database] {{Pharmacology}} == References == {{reflist}} * ''Basic and Clinical Pharmacology'' (9th Edition; Katzung): 1.4. Drug Biotransformation [[Category:Pharmacokinetics]] [[Category:Hepatology]] [[Category:Metabolism]] [[ja:薬物代謝]] [[pt:Metabolismo das drogas]] [[th:เมแทบอลิซึมของยา]]