Drug metabolism

Short description: Biochemical modification of drugs or foreign compounds by living organisms

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are organic compounds that are foreign to an organism's normal biochemistry, such as any drug, pollutant, or poison. These pathways are a form of biotransformation that are present in all major groups of organisms, a fact which may allude to an ancient origin. These reactions often act to detoxify poisonous compounds (although in some cases the intermediates in xenobiotic metabolism may cause toxic effects). The study of drug metabolism is one of the tenets of pharmacokinetics (PK) as metabolism (M), the fourth stage of LADME (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 of pharmaceutical drugs is an important aspect of pharmacology and medicine. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects multidrug resistance in infectious diseases and in chemotherapy for cancer, and the actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down during bioremediation, or persist in the environment. The enzymes of xenobiotic metabolism, particularly the glutathione S-transferases are also important in agriculture, since they may produce resistance to pesticides and herbicides.

Drug metabolism is divided into three phases. In phase I, enzymes such as Cytochrome 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 by transferase enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognized by efflux transporters and pumped out of cells. Drug metabolism often converts lipophilic compounds into hydrophilic products that are more readily excreted.[2]

## Contents

* 1 Permeability barriers and detoxification
* 2 Phases of detoxification
* 2.1 Phase I – modification
* 2.1.1 Oxidation
* 2.1.2 Reduction
* 2.1.3 Hydrolysis
* 2.2 Phase II – conjugation
* 2.3 Phase III – further modification and excretion
* 3 Endogenous toxins
* 4 Sites
* 5 Factors affecting drug metabolism
* 6 History
* 7 See also
* 8 References
* 9 Further reading
* 10 External links

## Permeability barriers and detoxification

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 normal metabolism. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity enzymatic systems.

All organisms use cell 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 through transport proteins that specifically select substrates from the extracellular mixture. This selective uptake means that most hydrophilic molecules cannot enter cells, since they are not recognized by any specific transporters.[4] In contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-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 the glyoxalase system, which removes the reactive aldehyde methylglyoxal,[5] and the various antioxidant systems that eliminate reactive oxygen species.[6]

##  Phases of detoxification

Phases I and II of the metabolism of a lipophilic xenobiotic.

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.

### Phase I – modification

In phase I, a variety of enzymes act to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalyzed by the cytochrome P-450-dependent mixed-function oxidase system. These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, 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-reactive oxyferryl species, according to the following scheme:[8]

O2 \+ NADPH + H+ \+ RH → NADP+ \+ H2O + ROH

Phase I reactions (also termed nonsynthetic reactions) may occur by oxidation, 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 a cytochrome P450 monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include phenothiazines, 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.

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 converts acetonitrile to glycolonitrile (HOCH2CN), which rapidly dissociates into formaldehyde and hydrogen cyanide.[9]

Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts.[10] This example of a biomimetic reaction tends to give products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceutical trimebutine, desmethyltrimebutine (nor-trimebutine), can be efficiently produced by in vitro oxidation of the commercially available drug. Hydroxylation of an N-methyl group leads to expulsion of a molecule of formaldehyde, while oxidation of the O-methyl groups takes place to a lesser extent.

#### Oxidation

* Cytochrome P450 monooxygenase system
* Flavin-containing monooxygenase system
* Alcohol dehydrogenase and aldehyde dehydrogenase
* Monoamine oxidase
* Co-oxidation by peroxidases

#### Reduction

* NADPH-cytochrome P450 reductase

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

* Reduced (ferrous) cytochrome P450

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

* Esterases and amidase
* Epoxide hydrolase

### Phase II – conjugation

In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathione (GSH), sulfate, glycine, or glucuronic acid. Sites on drugs where conjugation reactions occur include carboxy (-COOH), hydroxy (-OH), amino (NH2), and thiol (-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 produce active metabolites. The addition of large anionic groups (such as GSH) detoxifies reactive electrophiles 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 the glutathione S-transferases (GSTs).

Mechanism | Involved enzyme | Co-factor | Location | Sources

|
|
|
|

methylation | methyltransferase | S-adenosyl-L-methionine | liver, kidney, lung, CNS | [11]
sulfation | sulfotransferases | 3'-phosphoadenosine-5'-phosphosulfate | liver, kidney, intestine | [11]
acetylation |

* N-acetyltransferases
* bile acid-CoA:amino acid N-acyltransferases

| 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 | glutathione S-transferases | glutathione | liver, kidney | [11]
glycine conjugation | Two step process:

1. XM-ligase (forms a xenobiotic acyl-CoA)
2. Glycine N-acyltransferase (forms the glycine conjugate)

| glycine | liver, kidney | [12]

### Phase III – further modification and excretion

After phase II reactions, the xenobiotic conjugates may be further metabolized. A common example is the mercapturic acid pathway, which is the processing of glutathione (GSH) conjugates to N-acetylcysteine (mercapturic acid) conjugates.[13][14] Here, the γ-glutamate and glycine residues in the glutathione molecule are removed by gamma-glutamyl transpeptidase and dipeptidases. In the final step, the cysteine residue in the conjugate is acetylated.

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 the multidrug resistance protein (MRP) family.[15] These proteins are members of the family of ATP-binding cassette transporters and can catalyze the ATP-dependent transport of a huge variety of hydrophobic anions,[16] and thus act to remove phase II products to the extracellular medium, where they may be further metabolized or excreted.[17]

## Endogenous toxins

The detoxification of endogenous reactive metabolites such as peroxides and reactive aldehydes 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 the glyoxalase system, which acts to dispose of the reactive aldehyde methylglyoxal, and the various antioxidant systems that remove reactive oxygen species.

## 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 gastrointestinal tract (GI tract), where it enters the hepatic portal system through the portal vein, it becomes well-metabolized and is said to show the first pass effect.

Other sites of extrahepatic drug metabolism include epithelial cells of the GI tract, lungs, kidneys, and skin. These sites are usually responsible for localized toxicity reactions.

## Factors affecting 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 (CYP) is a crucial pathway in this regard. In general, anything that increases the rate of metabolism (e.g., enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true, as in enzyme 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. For example, chemotherapy prodrugs like cyclophosphamide (CPA) and ifosfamide (Ifex), which are initially inactive, become toxic as they are metabolized into cytotoxic compounds (such as phosphoramide mustard and chloroacetaldehyde) primarily from liver enzymes CYP2B6[18] and CYP3A4. Co-administration of a strong CYP inducer, such as phenytoin or rifampicin, accelerates metabolism and increases the rate of bioactivation 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 severe myelosuppression and hemorrhagic 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 the additive 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 in drug 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, like CYP2E1, 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 with overoxidation.[27]

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, sex differences or gut 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 of digoxin in the presence of Eggerthella lenta (E. lenta) in the microbiota.[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][31] 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.[32]

In general, drugs are metabolized more slowly in fetal, neonatal and elderly humans and animals than in adults. Inherited genetic variations in drug-metabolizing enzymes result in different catalytic activity levels. For example, N-acetyltransferases (involved in Phase 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 in NAT2 alleles distribution across different populations is high, and some ethnicities have a higher proportion of slow acetylators.[33] This variation in metabolizing capacity may have dramatic consequences, as the slow 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 [34] 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, like CYP2D6, CYP3A4, DPYD, UGT1A1. DPYD and UGT1A1 genotyping is now required before administration of the corresponding substrate compounds (5-FU and capecitabine for DPYD and irinotecan 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.[35]

Dose, frequency, route of administration, tissue distribution, and protein binding of the drug affect its metabolism.[36] Pathological factors can also influence drug metabolism, including liver, kidney, or heart disease.[37][38][39]

In silico modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects.[40] This can be used to identify individuals most at risk from adverse reaction.

## History

Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as benzaldehyde could be oxidized and conjugated to amino acids in the human body.[41] During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as methylation, acetylation, and sulfonation.

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 by Richard Williams of the book Detoxication mechanisms in 1947.[42] This modern biochemical research resulted in the identification of glutathione S-transferases in 1961,[43] followed by the discovery of cytochrome P450s in 1962,[44] and the realization of their central role in xenobiotic metabolism in 1963.[45][46]

## See also

* Biodegradation
* Microbial biodegradation

## References

1. ↑ Doogue, Matthew P.; Polasek, Thomas M. (February 2013). "The ABCD of clinical pharmacokinetics". Therapeutic Advances in Drug Safety 4 (1): 5–7. doi:10.1177/2042098612469335. ISSN 2042-0986. PMID 25083246.
2. ↑ Surendradoss, Jayakumar; Varghese, Alice; Deb, Subrata (2022-11-03), "Drug Metabolism: Detoxification and Xenobiotic Biotransformation" (in en), Biologically Active Small Molecules (New York: Apple Academic Press): pp. 287–332, doi:10.1201/9781003283119-17, ISBN 978-1-003-28311-9, https://www.taylorfrancis.com/books/9781003283119/chapters/10.1201/9781003283119-17, retrieved 2025-07-31
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8. ↑ "The catalytic pathway of cytochrome p450cam at atomic resolution". Science 287 (5458): 1615–22. March 2000. doi:10.1126/science.287.5458.1615. PMID 10698731. Bibcode: 2000Sci...287.1615S.
9. ↑ "Acetonitrile (EHC 154, 1993)". http://www.inchem.org/documents/ehc/ehc/ehc154.htm.
10. ↑ "Oxidation of antiparasitic 2-substituted quinolines using metalloporphyrin catalysts: scale-up of a biomimetic reaction for metabolite production of drug candidates". Org. Biomol. Chem. 6 (24): 4494–7. December 2008. doi:10.1039/b815963g. PMID 19039354.
11. ↑ 11.0 11.1 11.2 11.3 11.4 "Drug glucuronidation in clinical psychopharmacology". J Clin Psychopharmacol 21 (5): 500–15. October 2001. doi:10.1097/00004714-200110000-00008. PMID 11593076.
12. ↑ "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation". Expert Opinion on Drug Metabolism & Toxicology 9 (9): 1139–1153. September 2013. doi:10.1517/17425255.2013.796929. PMID 23650932. "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.".
13. ↑ "The Role of Glutathione and Glutathione S-Transferases in Mercapturic Acid Biosynthesis". Advances in Enzymology and Related Areas of Molecular Biology. 32. 1969. pp. 173–219. doi:10.1002/9780470122778.ch5. ISBN 978-0-470-12277-8.
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24. ↑ Yin, Ning; Ma, Wenzhe; Pei, Jianfeng; Ouyang, Qi; Tang, Chao; Lai, Luhua (2014-04-08). Aloy, Patrick. ed. "Synergistic and Antagonistic Drug Combinations Depend on Network Topology" (in en). PLOS ONE 9 (4). doi:10.1371/journal.pone.0093960. ISSN 1932-6203. PMID 24713621. Bibcode: 2014PLoSO...993960Y.
25. ↑ "Therapeutic index | Pharmacology Education Project" (in en). https://www.pharmacologyeducation.org/therapeutic-index.
26. ↑ Heit, Claire; Dong, Hongbin; Chen, Ying; Thompson, David C.; Deitrich, Richard A.; Vasiliou, Vasilis K. (2013). "The Role of CYP2E1 in Alcohol Metabolism and Sensitivity in the Central Nervous System". Cytochrome P450 2E1: Its Role in Disease and Drug Metabolism. Subcellular Biochemistry. 67. pp. 235–247. doi:10.1007/978-94-007-5881-0_8. ISBN 978-94-007-5880-3.
27. ↑ Oneta, Carl M.; Lieber, Charles S.; Li, JunJie; Rüttimann, Sigmund; Schmid, Beat; Lattmann, Jürg; Rosman, Alan S.; Seitz, Helmut K. (2002-01-01). "Dynamics of cytochrome P4502E1 activity in man: induction by ethanol and disappearance during withdrawal phase" (in English). Journal of Hepatology 36 (1): 47–52. doi:10.1016/S0168-8278(01)00223-9. ISSN 0168-8278. PMID 11804663. https://www.journal-of-hepatology.eu/article/S0168-8278(01)00223-9/abstract.
28. ↑ Wilson, Ian D.; Nicholson, Jeremy K. (January 2017). "Gut microbiome interactions with drug metabolism, efficacy, and toxicity". Translational Research: The Journal of Laboratory and Clinical Medicine 179: 204–222. doi:10.1016/j.trsl.2016.08.002. ISSN 1878-1810. PMID 27591027.
29. ↑ 29.0 29.1 "Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine". Nature Biotechnology 41 (9): 1320–1331. 19 January 2023. doi:10.1038/s41587-022-01628-0. PMID 36658342.
30. ↑ Chang, Yi-Cheng; Lee, Hsiao-Lin; Yang, Wenjin; Hsieh, Meng-Lun; Liu, Cai-Cin; Lee, Tung-Yuan; Huang, Jing-Yong; Nong, Jiun-Yi et al. (2023-09-25). "A common East-Asian ALDH2 mutation causes metabolic disorders and the therapeutic effect of ALDH2 activators" (in en). Nature Communications 14 (1): 5971. doi:10.1038/s41467-023-41570-6. ISSN 2041-1723. PMID 37749090. Bibcode: 2023NatCo..14.5971C.
31. ↑ Z, Asatani; A, Brooks (2024-01-20). "Aldehyde Dehydrogenase 2 Deficiency and Associated Health Risks in East Asian Populations: An Overview" (in en). Journal of Chemical Health Risks 14 (1): 824–840. doi:10.52783/jchr.v14.i01.2407. ISSN 2251-6727. https://www.jchr.org/index.php/JCHR/article/view/2407.
32. ↑ Lee, Jack (2019-12-12). "Alcohol, 'Asian glow' mutation may contribute to Alzheimer's disease, study finds" (in en-US). https://med.stanford.edu/news/all-news/2019/12/alcohol-asian-glow-mutation-may-contribute-to-alzheimers.html.
33. ↑ Gutiérrez-Virgen, Jorge E.; Piña-Pozas, Maricela; Hernández-Tobías, Esther A.; Taja-Chayeb, Lucia; López-González, Ma. de Lourdes; Meraz-Ríos, Marco A.; Gómez, Rocío (2023-04-06). "NAT2 global landscape: Genetic diversity and acetylation statuses from a systematic review". PLOS ONE 18 (4). doi:10.1371/journal.pone.0283726. ISSN 1932-6203. PMID 37023111. Bibcode: 2023PLoSO..1883726G.
34. ↑ Fukunaga, Koya; Kato, Ken; Okusaka, Takuji; Saito, Takeo; Ikeda, Masashi; Yoshida, Teruhiko; Zembutsu, Hitoshi; Iwata, Nakao et al. (2021-03-18). "Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity". Frontiers in Genetics 12. doi:10.3389/fgene.2021.652704. ISSN 1664-8021. PMID 33815485.
35. ↑ Muldoon, Megan; Beck, Mollie; Sebree, Nichlas; Yoder, Robin; Ritter, Stacey; Allen, Josiah D.; Alqahtani, Zuhair; Grund, Jaime et al. (February 2024). "Real-world implementation of DPYD and UGT1A1 pharmacogenetic testing in a community-based cancer center" (in en). Clinical and Translational Science 17 (2). doi:10.1111/cts.13704. ISSN 1752-8054.
36. ↑ Rn), Open Resources for Nursing (Open; Ernstmeyer, Kimberly; Christman, Elizabeth (2023), "Chapter 1 Pharmacokinetics & Pharmacodynamics" (in en), Nursing Pharmacology [Internet]. 2nd edition (Chippewa Valley Technical College), https://www.ncbi.nlm.nih.gov/books/NBK595006/, retrieved 2025-10-30
37. ↑ Lea-Henry, Tom N.; Carland, Jane E.; Stocker, Sophie L.; Sevastos, Jacob; Roberts, Darren M. (2018-06-22). "Clinical Pharmacokinetics in Kidney Disease" (in en-US). Clinical Journal of the American Society of Nephrology 13 (7): 1085–1095. doi:10.2215/CJN.00340118. ISSN 1555-9041. PMID 29934432.
38. ↑ Kato, R. (1977). "Drug metabolism under pathological and abnormal physiological states in animals and man". Xenobiotica; the Fate of Foreign Compounds in Biological Systems 7 (1–2): 25–92. doi:10.3109/00498257709036242. ISSN 0049-8254. PMID 322397.
39. ↑ Gandhi, Adarsh; Moorthy, Bhagavatula; Ghose, Romi (November 2012). "Drug disposition in pathophysiological conditions". Current Drug Metabolism 13 (9): 1327–1344. doi:10.2174/138920012803341302. ISSN 1875-5453. PMID 22746301.
40. ↑ "Simulation and prediction of in vivo drug metabolism in human populations from in vitro data". Nat Rev Drug Discov 6 (2): 140–8. February 2007. doi:10.1038/nrd2173. PMID 17268485. Bibcode: 2007NRvDD...6..140R.
41. ↑ Murphy PJ (June 2001). "Xenobiotic metabolism: a look from the past to the future". Drug Metab. Dispos. 29 (6): 779–80. PMID 11353742. http://dmd.aspetjournals.org/cgi/content/full/29/6/779. Retrieved 2012-12-29.
42. ↑ "Richard Tecwyn Williams: the man, his work, his impact". Drug Metab. Rev. 14 (3): 559–607. 1983. doi:10.3109/03602538308991399. PMID 6347595.
43. ↑ "An enzyme from rat liver catalysing conjugations with glutathione". Biochem. J. 79 (3): 516–24. June 1961. doi:10.1042/bj0790516. PMID 16748905.
44. ↑ "A new cytochrome in liver microsomes". J. Biol. Chem. 237 (4): 1375–6. April 1962. doi:10.1016/S0021-9258(18)60338-2. PMID 14482007.
45. ↑ Estabrook RW (December 2003). "A passion for P450s (remembrances of the early history of research on cytochrome P450)". Drug Metab. Dispos. 31 (12): 1461–73. doi:10.1124/dmd.31.12.1461. PMID 14625342.
46. ↑ "The light reversible carbon monoxide inhibition of steroid C-21 hydroxylase system in adrenal cortex". Biochem Z 338: 741–55. 1963. PMID 14087340.

## Further reading

* Molecular Responses to Xenobiotics. Elsevier. 2001. ISBN 0-345-42277-5. https://archive.org/details/molecularrespons0000unse.
* Ioannides C (2001). Enzyme Systems That Metabolise Drugs and Other Xenobiotics. John Wiley and Sons. ISBN 0-471-89466-4.
* Richardson M (1996). Environmental Xenobiotics. Taylor & Francis Ltd. ISBN 0-7484-0399-X.
* Ioannides C (1996). Cytochromes P450: Metabolic and Toxicological Aspects. CRC Press Inc. ISBN 0-8493-9224-1.
* Awasthi YC (2006). Toxicology of Glutathionine S-transferses. CRC Press Inc. ISBN 0-8493-2983-3.

## External links

* Databases
* Drug metabolism database
* Directory of P450-containing Systems
* University of Minnesota Biocatalysis/Biodegradation Database
* SPORCalc
* Drug metabolism
* Small Molecule Drug Metabolism
* Drug metabolism portal
* Microbial biodegradation
* Microbial Biodegradation, Bioremediation and Biotransformation
* History

* v
* t
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Pharmacology

Ligand (biochemistry)|

| Excitatory|

* Agonist
* Endogenous agonist
* Irreversible agonist
* Partial agonist
* Superagonist
* Physiological agonist

|

Inhibitory|

* Antagonist
* Competitive antagonist
* Irreversible antagonist
* Physiological antagonist
* Inverse agonist
* Enzyme inhibitor

|

* Drug
* Neurotransmitter
* Agonist-antagonist
* Pharmacophore

Pharmacodynamics|

| Activity at receptor|

* Mechanism of action
* Mode of action
* Binding
* Receptor (biochemistry)
* Desensitization (pharmacology)

|

Other effects of ligand|

* Selectivity (Binding, Functional)
* Pleiotropy (drugs)
* Non-specific effect of vaccines
* Adverse effects
* Toxicity (Neurotoxicity)

|

Analysis|

* Dose–response relationship
* Hill equation (biochemistry)
* Schild plot
* Del Castillo Katz model
* Cheng-Prussoff Equation
* Methods (Organ bath, Ligand binding assay, Patch-clamp)

|

Metrics|

* Efficacy
* Intrinsic activity
* Potency (EC50, IC50, ED50, LD50, TD50)
* Therapeutic index
* Affinity

|

Pharmacokinetics|

| Metrics|

* Loading dose
* Volume of distribution (Initial)
* Rate of infusion
* Onset of action
* Biological half-life
* Plasma protein binding
* Bioavailability

|

LADME|

* (L)ADME: (Liberation)
* Absorption
* Distribution
* Metabolism
* Excretion (Clearance)

|

* Compartment
* Bioequivalence

Related
fields|

| Neuroscience and psychology|

* Neuropsychopharmacology
* Neuropharmacology
* Psychopharmacology
* Electrophysiology

|

Medicine|

* Clinical pharmacology
* Pharmacy
* Medicinal chemistry
* Pharmacoepidemiology

|

Biochemistry and genetics|

* Pharmacoinformatics
* Pharmacogenetics
* Pharmacogenomics

|

Toxicology|

* Pharmacotoxicology
* Neurotoxicology

|

Drug discovery|

* Classical pharmacology
* Reverse pharmacology

|

* Photopharmacology
* Immunopharmacology
* Cell biology
* Physiology

Other|

* Coinduction (anaesthetics)
* Combination therapy
* Functional analog (chemistry)
* Polypharmacology
* Chemotherapy
* List of drugs
* WHO list of essential medicines

| Tolerance and resistance|

* Drug tolerance
* Tachyphylaxis
* Drug resistance
* Antibiotic resistance
* Multiple drug resistance

|

Antimicrobial pharmacology|

* Antimicrobial pharmacodynamics
* Minimum inhibitory concentration
* Bacteriostatic
* Minimum bactericidal concentration
* Bactericide

|

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