286:. 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. 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:
267:
3254:
1551:
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
245:
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
241:
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
206:
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. The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of
1554:
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
431:
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
782:
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
783:
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
916:. 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
537:
These reactions are catalysed by a large group of broad-specificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups. One of the most important classes of this group is that of the
1555:
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.
995:) and many more and increased toxicity as well as drug adverse reactions in slow acetylators have been widely reported. Similar phenomenons of altered metabolism due to inherited variations have been described for other drug-metabolising enzymes, like
1084:
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
1056:
modelling and simulation methods allow drug metabolism to be predicted in virtual patient populations prior to performing clinical studies in human subjects. This can be used to identify individuals most at risk from adverse reaction.
1428:
Akagah B, Lormier AT, Fournet A, Figadère B (December 2008). "Oxidation of antiparasitic 2-substituted quinolines using metalloporphyrin catalysts: scale-up of a biomimetic reaction for metabolite production of drug candidates".
330:, 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
1696:
Commandeur JN, Stijntjes GJ, Vermeulen NP (June 1995). "Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics".
1516:
Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA (September 2013). "Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation".
765:
and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions, and thus act to remove phase II products to the extracellular medium, where they may be further metabolized or excreted.
819:
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
970:
alleles distribution across different populations is high and some ethnicities have higher proportion of slow acetylators. This variation in metabolising capacity may have dramatic consequences, as the
222:
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
375:, 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
824:, 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
885:. 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.
1902:
Muldoon, Megan; Beck, Mollie; Sebree, Nichlas; Yoder, Robin; Ritter, Stacey; Allen, Josiah D.; Alqahtani, Zuhair; Grund, Jaime; Philips, Brooke; Hesse, Kristina; El Rouby, Nihal (February 2024).
274:
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.
1552:
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. ...
1356:
Schlichting I, Berendzen J, Chu K, Stock AM, Maves SA, Benson DE, Sweet RM, Ringe D, Petsko GA, Sligar SG (March 2000). "The catalytic pathway of cytochrome p450cam at atomic resolution".
757:
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
1069:
could be oxidized and conjugated to amino acids in the human body. During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as
1776:
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).
1008:
526:(-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
178:
introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by
318:, 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
282:
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 catalysed by the
1845:"Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity"
954:. Inherited genetic variations in drug metabolising enzymes result in their different catalytic activity levels. For example, N-acetyltransferases (involved in
1843:
Fukunaga, Koya; Kato, Ken; Okusaka, Takuji; Saito, Takeo; Ikeda, Masashi; Yoshida, Teruhiko; Zembutsu, Hitoshi; Iwata, Nakao; Mushiroda, Taisei (2021-03-18).
1065:
Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as
1097:-transferases in 1961, followed by the discovery of cytochrome P450s in 1962, and the realization of their central role in xenobiotic metabolism in 1963.
599:
432:
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 → O
1612:
Homolya L, Váradi A, Sarkadi B (2003). "Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate".
623:
865:
The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The
2211:
Estabrook RW, Cooper DY, Rosenthal O (1963). "The light reversible carbon monoxide inhibition of steroid C-21 hydroxylase system in adrenal cortex".
1004:
322:
monooxygenase (often abbreviated CYP), NADPH and oxygen. The classes of pharmaceutical drugs that utilize this method for their metabolism include
242:
metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.
182:
enzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by
340:
A common Phase I oxidation involves conversion of a C-H bond to a C-OH. This reaction sometimes converts a pharmacologically inactive compound (a
1657:"Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance"
726:
After phase II reactions, the xenobiotic conjugates may be further metabolized. A common example is the processing of glutathione conjugates to
2436:
393:
348:). Simple hydrolysis in the stomach is normally an innocuous reaction, however there are exceptions. For example, phase I metabolism converts
31:
1031:
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.
2528:
2493:
896:
factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (e.g.,
866:
115:. For example, the rate of metabolism determines the duration and intensity of a drug's pharmacologic action. Drug metabolism also affects
371:
reaction tends to give products that often contains the Phase I metabolites. As an example, the major metabolite of the pharmaceutical
3222:
2332:
2313:
2294:
2275:
2256:
2019:
1588:
1188:
Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y (September 2003). "Impact of drug transporter studies on drug discovery and development".
1233:"The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life"
3212:
762:
1407:
3152:
2645:
1951:
Rostami-Hodjegan A, Tucker GT (February 2007). "Simulation and prediction of in vivo drug metabolism in human populations from
882:
874:
2680:
3207:
2903:
2814:
1567:
Boyland E, Chasseaud LF (1969). "The role of glutathione and glutathione S-transferases in mercapturic acid biosynthesis".
211:. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity
3132:
2757:
739:
2155:
1167:
100:) of the drug's transit through the body that involves the breakdown of the drug so that it can be excreted by the body.
2685:
2176:
Estabrook RW (December 2003). "A passion for P450s (remembrances of the early history of research on cytochrome P450)".
1321:
Guengerich FP (June 2001). "Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity".
808:
230:
molecules cannot enter cells, since they are not recognised by any specific transporters. In contrast, the diffusion of
156:
534:
and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.
367:
Phase I metabolism of drug candidates can be simulated in the laboratory using non-enzyme catalysts. This example of a
2875:
2367:
651:
1034:
Dose, frequency, route of administration, tissue distribution and protein binding of the drug affect its metabolism.
3244:
2610:
2429:
344:) to a pharmacologically active one. By the same token, Phase I can turn a nontoxic molecule into a poisonous one (
84:
present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to
3289:
3122:
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901:
700:
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539:
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160:
3187:
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2523:
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319:
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in xenobiotic metabolism can themselves cause toxic effects). The study of drug metabolism is the object of
3074:
2835:
2810:
2745:
2634:
2518:
1473:
Liston HL, Markowitz JS, DeVane CL (October 2001). "Drug glucuronidation in clinical psychopharmacology".
925:
842:
402:
226:
that specifically select substrates from the extracellular mixture. This selective uptake means that most
1904:"Real-world implementation of DPYD and UGT1A1 pharmacogenetic testing in a community-based cancer center"
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183:
144:
132:
89:
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104:
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1980:
1637:
1542:
1498:
1213:
527:
120:
1729:"Genome-scale metabolic reconstruction of 7,302 human microorganisms for personalized medicine"
234:
compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude
30:
This article is about the scientific concept of drug metabolism. For alternative medicine, see
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2011:
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1964:
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1915:
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1815:
1797:
1778:"NAT2 global landscape: Genetic diversity and acetylation statuses from a systematic review"
1748:
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140:
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93:
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genotyping is now required before administration of the corresponding substrate compounds (
3258:
3177:
3052:
2840:
2825:
2533:
2483:
2406:
2392:
838:
646:
503:
283:
1999:
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can recognize and remove them. Examples of these specific detoxification systems are the
2040:
Neuberger A, Smith RL (1983). "Richard Tecwyn
Williams: the man, his work, his impact".
1936:
1820:
1793:
1777:
1753:
1728:
1369:
1093:
in 1947. This modern biochemical research resulted in the identification of glutathione
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combines with the newly incorporated functional group to form a highly polar conjugate.
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3147:
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2101:
2076:
1879:
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758:
727:
636:
152:
85:
2142:
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266:
17:
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2659:
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1984:
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1399:
1298:
1281:
821:
788:
731:
323:
219:
148:
61:
1546:
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3003:
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2445:
1641:
1502:
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1024:
1020:
988:
531:
376:
357:
349:
345:
124:
108:
1377:
1217:
1802:
1530:
958:
reactions), individual variation creates a group of people who acetylate slowly (
3227:
2714:
2690:
1078:
1074:
1070:
984:
881:
the duration and intensity of the drug action. The opposite is also true, as in
825:
792:
743:
676:
611:
567:
491:
372:
327:
315:
179:
72:, which are compounds foreign to an organism's normal biochemistry, such as any
1744:
139:
of enzymes involved in xenobiotic metabolism are a common reason for hazardous
3107:
3039:
2931:
2706:
2125:
2053:
1861:
1580:
1137:
1028:
992:
751:
589:
413:
368:
331:
311:
231:
227:
208:
207:
xenobiotic compounds from the complex mixture of chemicals involved in normal
191:
187:
69:
41:
1927:
1870:
1811:
486:
In subsequent phase II reactions, these activated xenobiotic metabolites are
2885:
1625:
980:
966:), split roughly 50:50 in the population of Canada. However, variability in
905:
694:
303:
195:
168:
164:
2224:
2197:
2189:
2151:
2110:
2015:
1976:
1888:
1829:
1762:
1682:
1633:
1538:
1494:
1450:
1385:
1342:
1209:
159:
in the environment. The enzymes of xenobiotic metabolism, particularly the
2061:
1710:
1598:
1307:
1266:
1163:
174:
Drug metabolism is divided into three phases. In phase I, enzymes such as
27:
Biochemical modification of drugs or foreign compounds by living organisms
3007:
2979:
2966:
2735:
2655:
936:
779:
775:
747:
530:. The addition of large anionic groups (such as GSH) detoxifies reactive
511:
466:
379:, while oxidation of the O-methyl groups takes place to a lesser extent.
251:
112:
49:
857:. These sites are usually responsible for localized toxicity reactions.
163:
are also important in agriculture, since they may produce resistance to
2468:
940:
917:
735:
708:
507:
499:
495:
470:
449:, in which it gains a free-radical electron, then promptly loses it to
341:
2092:
1919:
1334:
1248:
1201:
1442:
1043:
1000:
996:
947:
850:
450:
212:
128:
77:
53:
1968:
302:
Phase I reactions (also termed nonsynthetic reactions) may occur by
2077:"An enzyme from rat liver catalysing conjugations with glutathione"
1571:. Advances in Enzymology – and Related Areas of Molecular Biology.
1047:
1039:
951:
943:
932:
812:
523:
515:
307:
265:
254:
methylglyoxal, and the various antioxidant systems that eliminate
235:
64:"stranger" and biotic "related to living beings") is the set of
2860:
2753:
2749:
2551:
976:
854:
846:
97:
73:
45:
2418:
2414:
1727:
Heinken A, Hertel J, Acharya G, et al. (19 January 2023).
928:) accounts for some of the variability in the effect of drugs.
869:
is a crucial pathway in this regard. In general, anything that
815:
cell is the principal organ of drug metabolism, although every
2393:
774:
The detoxification of endogenous reactive metabolites such as
1655:
König J, Nies AT, Cui Y, Leier I, Keppler D (December 1999).
270:
Phases I and II of the metabolism of a lipophilic xenobiotic.
2363:
University of
Minnesota Biocatalysis/Biodegradation Database
2000:"Xenobiotic metabolism: a look from the past to the future"
506:. Sites on drugs where conjugation reactions occur include
151:
determining whether a pollutant will be broken down during
2268:
Enzyme
Systems That Metabolise Drugs and Other Xenobiotics
761:(MRP) family. These proteins are members of the family of
2362:
284:
cytochrome P-450-dependent mixed-function oxidase system
186:
and pumped out of cells. Drug metabolism often converts
828:, it becomes well-metabolized and is said to show the
3242:
2306:
979:
enzyme is a primary metaboliser of antituberculosis (
661:
liver, kidney, intestine, lung, skin, prostate, brain
738:
residues in the glutathione molecule are removed by
3200:
3160:
3116:
3065:
3038:
3002:
2965:
2926:
2917:
2853:
2798:
2789:
2728:
2673:
2622:
2584:
2575:
2506:
2461:
2452:
2244:
1519:Expert Opinion on Drug Metabolism & Toxicology
931:In general, drugs are metabolized more slowly in
787:, which acts to dispose of the reactive aldehyde
445:During reduction reactions, a chemical can enter
877:) of a pharmacologically active metabolite will
88:poisonous compounds (although in some cases the
1038:can also influence drug metabolism, including
722:Phase III – further modification and excretion
238:-soluble xenobiotics using membrane barriers.
2430:
1468:
1466:
1464:
1462:
1460:
1282:"Oxidative stress: oxidants and antioxidants"
8:
975:are more prone to dose-dependent toxicity.
624:bile acid-CoA:amino acid N-acyltransferases
3197:
3157:
3062:
3035:
2999:
2962:
2923:
2850:
2795:
2725:
2670:
2619:
2581:
2503:
2458:
2437:
2423:
2415:
2325:Toxicology of Glutathionine S-transferses
2141:
2100:
1935:
1878:
1860:
1819:
1801:
1752:
1672:
1297:
1256:
1153:
730:(mercapturic acid) conjugates. Here, the
2075:Booth J, Boyland E, Sims P (June 1961).
1131:
1129:
1127:
544:
202:Permeability barriers and detoxification
3249:
1722:
1720:
1136:Jakoby WB, Ziegler DM (December 1990).
1123:
837:Other sites of drug metabolism include
143:. These pathways are also important in
96:. Metabolism is one of the stages (see
2126:"A new cytochrome in liver microsomes"
924:in the microbiota. Genetic variation (
394:Flavin-containing monooxygenase system
68:that modify the chemical structure of
635:liver, lung, spleen, gastric mucosa,
600:3'-phosphoadenosine-5'-phosphosulfate
32:Detoxification (alternative medicine)
7:
2358:Directory of P450-containing Systems
1569:Adv. Enzymol. Relat. Areas Mol. Biol
867:Cytochrome P450 monooxygenase system
389:Cytochrome P450 monooxygenase system
147:, with the xenobiotic metabolism of
962:) and those who acetylate quickly (
356:CN, which rapidly dissociates into
131:, and the actions of some drugs as
3223:Minimum bactericidal concentration
2247:Molecular Responses to Xenobiotics
1908:Clinical and Translational Science
25:
861:Factors affecting drug metabolism
763:ATP-binding cassette transporters
440:Reduced (ferrous) cytochrome P450
3252:
3213:Minimum inhibitory concentration
2403:History of Xenobiotic Metabolism
1487:10.1097/00004714-200110000-00008
1299:10.1113/expphysiol.1997.sp004024
3153:WHO list of essential medicines
2646:Non-specific effect of vaccines
2158:from the original on 2009-06-21
2022:from the original on 2009-06-21
1410:from the original on 2017-05-22
1170:from the original on 2009-06-21
426:NADPH-cytochrome P450 reductase
194:products that are more readily
80:. These pathways are a form of
3208:Antimicrobial pharmacodynamics
2378:Small Molecule Drug Metabolism
2124:Omura T, Sato R (April 1962).
1400:"Acetonitrile (EHC 154, 1993)"
873:the rate of metabolism (e.g.,
52:, usually through specialized
1:
3133:Functional analog (chemistry)
2409: (archived July 13, 2007)
2143:10.1016/S0021-9258(18)60338-2
1674:10.1016/S0005-2736(99)00169-8
1378:10.1126/science.287.5458.1615
1155:10.1016/S0021-9258(17)45272-0
1138:"The enzymes of detoxication"
740:gamma-glutamyl transpeptidase
703:(forms the glycine conjugate)
697:(forms a xenobiotic acyl-CoA)
490:with charged species such as
250:, which removes the reactive
2686:Hill equation (biochemistry)
2289:. Taylor & Francis Ltd.
1803:10.1371/journal.pone.0283726
1531:10.1517/17425255.2013.796929
809:smooth endoplasmic reticulum
759:multidrug resistance protein
750:residue in the conjugate is
652:UDP-glucuronosyltransferases
294:+ NADPH + H + RH → NADP + H
1231:Thornalley PJ (July 1990).
3311:
3201:Antimicrobial pharmacology
2681:Dose–response relationship
2611:Desensitization (medicine)
2243:Parvez H, Reiss C (2001).
1745:10.1038/s41587-022-01628-0
983:), some antihypertensive (
672:glutathione S-transferases
540:glutathione S-transferases
161:glutathione S-transferases
107:is an important aspect of
29:
3123:Coinduction (anesthetics)
2389:Microbial biodegradation
2287:Environmental Xenobiotics
2054:10.3109/03602538308991399
1862:10.3389/fgene.2021.652704
1581:10.1002/9780470122778.ch5
987:), anti-arrythmic drugs (
902:enterohepatic circulation
746:. In the final step, the
701:Glycine N-acyltransferase
56:systems. More generally,
3188:Multiple drug resistance
3161:Tolerance and resistance
2529:Physiological antagonist
2353:Drug metabolism database
1112:Microbial biodegradation
604:liver, kidney, intestine
582:liver, kidney, lung, CNS
262:Phases of detoxification
176:cytochrome P450 oxidases
2939:Neuropsychopharmacology
2701:Cheng-Prussoff Equation
2696:Del Castillo Katz model
2623:Other effects of ligand
2606:Receptor (biochemistry)
2524:Irreversible antagonist
2270:. John Wiley and Sons.
1998:Murphy PJ (June 2001).
1626:10.1002/biof.5520170111
1091:Detoxication mechanisms
797:reactive oxygen species
668:glutathione conjugation
578:S-adenosyl-L-methionine
482:Phase II – conjugation
256:reactive oxygen species
3075:Classical pharmacology
2836:Plasma protein binding
2811:Volume of distribution
2519:Competitive antagonist
2383:Drug metabolism portal
2190:10.1124/dmd.31.12.1461
1661:Biochim. Biophys. Acta
1475:J Clin Psychopharmacol
843:gastrointestinal tract
403:aldehyde dehydrogenase
278:Phase I – modification
271:
18:Xenobiotic conjugation
3183:Antibiotic resistance
2975:Clinical pharmacology
2494:Physiological agonist
2454:Ligand (biochemistry)
2285:Richardson M (1996).
1849:Frontiers in Genetics
1280:Sies H (March 1997).
399:Alcohol dehydrogenase
269:
145:environmental science
58:xenobiotic metabolism
3080:Reverse pharmacology
2990:Pharmacoepidemiology
2831:Biological half-life
2711:Ligand binding assay
2585:Activity at receptor
2479:Irreversible agonist
2304:Ioannides C (1996).
2266:Ioannides C (2001).
1733:Nature Biotechnology
1036:Pathological factors
991:), antidepressants (
807:Quantitatively, the
795:systems that remove
619:N-acetyltransferases
117:multidrug resistance
105:pharmaceutical drugs
3128:Combination therapy
3016:Pharmacoinformatics
2985:Medicinal chemistry
2591:Mechanism of action
2323:Awasthi YC (2006).
1957:Nat Rev Drug Discov
1794:2023PLoSO..1883726G
1370:2000Sci...287.1615S
920:in the presence of
688:glycine conjugation
657:UDP-glucuronic acid
184:efflux transporters
121:infectious diseases
42:metabolic breakdown
3098:Immunopharmacology
3048:Pharmacotoxicology
2949:Psychopharmacology
2741:Intrinsic activity
2641:Pleiotropy (drugs)
2562:Agonist-antagonist
2474:Endogenous agonist
2178:Drug Metab. Dispos
2004:Drug Metab. Dispos
1323:Chem. Res. Toxicol
791:, and the various
691:Two step process:
528:active metabolites
272:
224:transport proteins
218:All organisms use
103:The metabolism of
66:metabolic pathways
3240:
3239:
3236:
3235:
3196:
3195:
3093:Photopharmacology
3088:
3087:
3061:
3060:
3034:
3033:
2998:
2997:
2961:
2960:
2954:Electrophysiology
2944:Neuropharmacology
2899:
2898:
2849:
2848:
2785:
2784:
2772:Therapeutic index
2724:
2723:
2669:
2668:
2618:
2617:
2547:
2546:
2502:
2501:
2327:. CRC Press Inc.
2308:. CRC Press Inc.
2093:10.1042/bj0790516
1920:10.1111/cts.13704
1431:Org. Biomol. Chem
1364:(5458): 1615–22.
1335:10.1021/tx0002583
1249:10.1042/bj2690001
1202:10.1124/pr.55.3.1
964:rapid acetylators
922:Eggerthella lenta
883:enzyme inhibition
831:first pass effect
817:biological tissue
785:glyoxalase system
770:Endogenous toxins
719:
718:
631:acetyl coenzyme A
595:sulfotransferases
573:methyltransferase
562:
476:Epoxide hydrolase
408:Monoamine oxidase
248:glyoxalase system
141:drug interactions
82:biotransformation
16:(Redirected from
3302:
3290:Pharmacokinetics
3257:
3256:
3255:
3248:
3198:
3158:
3138:Polypharmacology
3063:
3036:
3026:Pharmacogenomics
3021:Pharmacogenetics
3000:
2963:
2924:
2851:
2821:Rate of infusion
2796:
2791:Pharmacokinetics
2726:
2671:
2620:
2582:
2577:Pharmacodynamics
2557:Neurotransmitter
2539:Enzyme inhibitor
2504:
2459:
2439:
2432:
2425:
2416:
2374:Drug metabolism
2338:
2319:
2300:
2281:
2262:
2250:
2229:
2228:
2208:
2202:
2201:
2173:
2167:
2166:
2164:
2163:
2145:
2121:
2115:
2114:
2104:
2072:
2066:
2065:
2037:
2031:
2030:
2028:
2027:
1995:
1989:
1988:
1948:
1942:
1941:
1939:
1899:
1893:
1892:
1882:
1864:
1840:
1834:
1833:
1823:
1805:
1773:
1767:
1766:
1756:
1739:(9): 1320–1331.
1724:
1715:
1714:
1693:
1687:
1686:
1676:
1652:
1646:
1645:
1609:
1603:
1602:
1564:
1558:
1557:
1525:(9): 1139–1153.
1513:
1507:
1506:
1470:
1455:
1454:
1443:10.1039/b815963g
1425:
1419:
1418:
1416:
1415:
1396:
1390:
1389:
1353:
1347:
1346:
1318:
1312:
1311:
1301:
1277:
1271:
1270:
1260:
1228:
1222:
1221:
1185:
1179:
1178:
1176:
1175:
1157:
1133:
1087:Richard Williams
973:slow acetylators
960:slow acetylators
898:pharmacogenetics
875:enzyme induction
839:epithelial cells
560:
545:
455:superoxide anion
412:Co-oxidation by
362:hydrogen cyanide
94:pharmacokinetics
60:(from the Greek
21:
3310:
3309:
3305:
3304:
3303:
3301:
3300:
3299:
3265:
3264:
3263:
3253:
3251:
3243:
3241:
3232:
3192:
3178:Drug resistance
3156:
3112:
3084:
3057:
3053:Neurotoxicology
3030:
2994:
2957:
2919:
2913:
2895:
2845:
2841:Bioavailability
2826:Onset of action
2781:
2720:
2665:
2614:
2571:
2543:
2534:Inverse agonist
2498:
2484:Partial agonist
2448:
2443:
2407:Wayback Machine
2346:
2341:
2335:
2322:
2316:
2303:
2297:
2284:
2278:
2265:
2259:
2242:
2238:
2236:Further reading
2233:
2232:
2210:
2209:
2205:
2184:(12): 1461–73.
2175:
2174:
2170:
2161:
2159:
2123:
2122:
2118:
2074:
2073:
2069:
2042:Drug Metab. Rev
2039:
2038:
2034:
2025:
2023:
1997:
1996:
1992:
1969:10.1038/nrd2173
1950:
1949:
1945:
1901:
1900:
1896:
1842:
1841:
1837:
1788:(4): e0283726.
1775:
1774:
1770:
1726:
1725:
1718:
1695:
1694:
1690:
1654:
1653:
1649:
1620:(1–4): 103–14.
1611:
1610:
1606:
1591:
1566:
1565:
1561:
1553:
1515:
1514:
1510:
1472:
1471:
1458:
1427:
1426:
1422:
1413:
1411:
1398:
1397:
1393:
1355:
1354:
1350:
1320:
1319:
1315:
1279:
1278:
1274:
1230:
1229:
1225:
1187:
1186:
1182:
1173:
1171:
1148:(34): 20715–8.
1135:
1134:
1125:
1120:
1103:
1063:
910:sex differences
863:
805:
772:
724:
647:glucuronidation
551:Involved enzyme
521:
504:glucuronic acid
484:
463:
435:
422:
385:
355:
320:cytochrome P450
297:
293:
280:
264:
204:
190:compounds into
38:Drug metabolism
35:
28:
23:
22:
15:
12:
11:
5:
3308:
3306:
3298:
3297:
3295:Biodegradation
3292:
3287:
3282:
3277:
3267:
3266:
3262:
3261:
3238:
3237:
3234:
3233:
3231:
3230:
3225:
3220:
3218:Bacteriostatic
3215:
3210:
3204:
3202:
3194:
3193:
3191:
3190:
3185:
3180:
3175:
3170:
3168:Drug tolerance
3164:
3162:
3155:
3150:
3148:Lists of drugs
3145:
3140:
3135:
3130:
3125:
3120:
3118:
3114:
3113:
3111:
3110:
3105:
3100:
3095:
3089:
3086:
3085:
3083:
3082:
3077:
3071:
3069:
3067:Drug discovery
3059:
3058:
3056:
3055:
3050:
3044:
3042:
3032:
3031:
3029:
3028:
3023:
3018:
3012:
3010:
2996:
2995:
2993:
2992:
2987:
2982:
2977:
2971:
2969:
2959:
2958:
2956:
2951:
2946:
2941:
2936:
2934:
2921:
2915:
2914:
2912:
2911:
2909:Bioequivalence
2906:
2900:
2897:
2896:
2894:
2893:
2883:
2878:
2873:
2868:
2857:
2855:
2847:
2846:
2844:
2843:
2838:
2833:
2828:
2823:
2818:
2808:
2802:
2800:
2793:
2787:
2786:
2783:
2782:
2780:
2779:
2774:
2769:
2743:
2738:
2732:
2730:
2722:
2721:
2719:
2718:
2703:
2698:
2693:
2688:
2683:
2677:
2675:
2667:
2666:
2664:
2663:
2653:
2651:Adverse effect
2648:
2643:
2638:
2626:
2624:
2616:
2615:
2613:
2608:
2603:
2598:
2596:Mode of action
2593:
2588:
2586:
2579:
2573:
2572:
2570:
2569:
2564:
2559:
2554:
2548:
2545:
2544:
2542:
2541:
2536:
2531:
2526:
2521:
2516:
2510:
2508:
2500:
2499:
2497:
2496:
2491:
2486:
2481:
2476:
2471:
2465:
2463:
2456:
2450:
2449:
2444:
2442:
2441:
2434:
2427:
2419:
2413:
2412:
2411:
2410:
2397:
2396:
2395:
2387:
2386:
2385:
2380:
2372:
2371:
2370:
2365:
2360:
2355:
2345:
2344:External links
2342:
2340:
2339:
2333:
2320:
2314:
2301:
2295:
2282:
2276:
2263:
2257:
2239:
2237:
2234:
2231:
2230:
2203:
2168:
2116:
2067:
2048:(3): 559–607.
2032:
1990:
1943:
1894:
1835:
1768:
1716:
1705:(2): 271–330.
1699:Pharmacol. Rev
1688:
1647:
1604:
1589:
1559:
1508:
1456:
1437:(24): 4494–7.
1420:
1404:www.inchem.org
1391:
1348:
1313:
1272:
1223:
1190:Pharmacol. Rev
1180:
1122:
1121:
1119:
1116:
1115:
1114:
1109:
1107:Biodegradation
1102:
1099:
1062:
1059:
914:gut microbiota
862:
859:
804:
801:
771:
768:
728:acetylcysteine
723:
720:
717:
716:
714:
711:
706:
705:
704:
698:
689:
685:
684:
682:
679:
674:
669:
665:
664:
662:
659:
654:
649:
643:
642:
640:
639:, lymphocytes
633:
628:
627:
626:
621:
614:
608:
607:
605:
602:
597:
592:
586:
585:
583:
580:
575:
570:
564:
563:
558:
555:
552:
549:
519:
483:
480:
479:
478:
473:
462:
459:
447:futile cycling
443:
442:
433:
429:
428:
421:
418:
417:
416:
410:
405:
396:
391:
384:
381:
353:
324:phenothiazines
300:
299:
295:
291:
279:
276:
263:
260:
220:cell membranes
203:
200:
153:bioremediation
149:microorganisms
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
3307:
3296:
3293:
3291:
3288:
3286:
3283:
3281:
3278:
3276:
3273:
3272:
3270:
3260:
3250:
3246:
3229:
3226:
3224:
3221:
3219:
3216:
3214:
3211:
3209:
3206:
3205:
3203:
3199:
3189:
3186:
3184:
3181:
3179:
3176:
3174:
3173:Tachyphylaxis
3171:
3169:
3166:
3165:
3163:
3159:
3154:
3151:
3149:
3146:
3144:
3141:
3139:
3136:
3134:
3131:
3129:
3126:
3124:
3121:
3119:
3115:
3109:
3106:
3104:
3101:
3099:
3096:
3094:
3091:
3090:
3081:
3078:
3076:
3073:
3072:
3070:
3068:
3064:
3054:
3051:
3049:
3046:
3045:
3043:
3041:
3037:
3027:
3024:
3022:
3019:
3017:
3014:
3013:
3011:
3009:
3005:
3001:
2991:
2988:
2986:
2983:
2981:
2978:
2976:
2973:
2972:
2970:
2968:
2964:
2955:
2952:
2950:
2947:
2945:
2942:
2940:
2937:
2935:
2933:
2929:
2925:
2922:
2916:
2910:
2907:
2905:
2902:
2901:
2891:
2887:
2884:
2882:
2879:
2877:
2874:
2872:
2869:
2866:
2862:
2859:
2858:
2856:
2852:
2842:
2839:
2837:
2834:
2832:
2829:
2827:
2824:
2822:
2819:
2816:
2812:
2809:
2807:
2804:
2803:
2801:
2797:
2794:
2792:
2788:
2778:
2775:
2773:
2770:
2767:
2763:
2759:
2755:
2751:
2747:
2744:
2742:
2739:
2737:
2734:
2733:
2731:
2727:
2716:
2712:
2708:
2704:
2702:
2699:
2697:
2694:
2692:
2689:
2687:
2684:
2682:
2679:
2678:
2676:
2672:
2661:
2660:Neurotoxicity
2657:
2654:
2652:
2649:
2647:
2644:
2642:
2639:
2636:
2632:
2629:Selectivity (
2628:
2627:
2625:
2621:
2612:
2609:
2607:
2604:
2602:
2599:
2597:
2594:
2592:
2589:
2587:
2583:
2580:
2578:
2574:
2568:
2567:Pharmacophore
2565:
2563:
2560:
2558:
2555:
2553:
2550:
2549:
2540:
2537:
2535:
2532:
2530:
2527:
2525:
2522:
2520:
2517:
2515:
2512:
2511:
2509:
2505:
2495:
2492:
2490:
2487:
2485:
2482:
2480:
2477:
2475:
2472:
2470:
2467:
2466:
2464:
2460:
2457:
2455:
2451:
2447:
2440:
2435:
2433:
2428:
2426:
2421:
2420:
2417:
2408:
2404:
2401:
2400:
2398:
2394:
2391:
2390:
2388:
2384:
2381:
2379:
2376:
2375:
2373:
2369:
2366:
2364:
2361:
2359:
2356:
2354:
2351:
2350:
2348:
2347:
2343:
2336:
2334:0-8493-2983-3
2330:
2326:
2321:
2317:
2315:0-8493-9224-1
2311:
2307:
2302:
2298:
2296:0-7484-0399-X
2292:
2288:
2283:
2279:
2277:0-471-89466-4
2273:
2269:
2264:
2260:
2258:0-345-42277-5
2254:
2249:
2248:
2241:
2240:
2235:
2226:
2222:
2218:
2214:
2207:
2204:
2199:
2195:
2191:
2187:
2183:
2179:
2172:
2169:
2157:
2153:
2149:
2144:
2139:
2136:(4): 1375–6.
2135:
2131:
2130:J. Biol. Chem
2127:
2120:
2117:
2112:
2108:
2103:
2098:
2094:
2090:
2087:(3): 516–24.
2086:
2082:
2078:
2071:
2068:
2063:
2059:
2055:
2051:
2047:
2043:
2036:
2033:
2021:
2017:
2013:
2010:(6): 779–80.
2009:
2005:
2001:
1994:
1991:
1986:
1982:
1978:
1974:
1970:
1966:
1962:
1958:
1954:
1947:
1944:
1938:
1933:
1929:
1925:
1921:
1917:
1913:
1909:
1905:
1898:
1895:
1890:
1886:
1881:
1876:
1872:
1868:
1863:
1858:
1854:
1850:
1846:
1839:
1836:
1831:
1827:
1822:
1817:
1813:
1809:
1804:
1799:
1795:
1791:
1787:
1783:
1779:
1772:
1769:
1764:
1760:
1755:
1750:
1746:
1742:
1738:
1734:
1730:
1723:
1721:
1717:
1712:
1708:
1704:
1700:
1692:
1689:
1684:
1680:
1675:
1670:
1667:(2): 377–94.
1666:
1662:
1658:
1651:
1648:
1643:
1639:
1635:
1631:
1627:
1623:
1619:
1615:
1608:
1605:
1600:
1596:
1592:
1590:9780470122778
1586:
1582:
1578:
1574:
1570:
1563:
1560:
1556:
1548:
1544:
1540:
1536:
1532:
1528:
1524:
1520:
1512:
1509:
1504:
1500:
1496:
1492:
1488:
1484:
1481:(5): 500–15.
1480:
1476:
1469:
1467:
1465:
1463:
1461:
1457:
1452:
1448:
1444:
1440:
1436:
1432:
1424:
1421:
1409:
1405:
1401:
1395:
1392:
1387:
1383:
1379:
1375:
1371:
1367:
1363:
1359:
1352:
1349:
1344:
1340:
1336:
1332:
1329:(6): 611–50.
1328:
1324:
1317:
1314:
1309:
1305:
1300:
1295:
1291:
1287:
1283:
1276:
1273:
1268:
1264:
1259:
1254:
1250:
1246:
1242:
1238:
1234:
1227:
1224:
1219:
1215:
1211:
1207:
1203:
1199:
1196:(3): 425–61.
1195:
1191:
1184:
1181:
1169:
1165:
1161:
1156:
1151:
1147:
1143:
1142:J. Biol. Chem
1139:
1132:
1130:
1128:
1124:
1117:
1113:
1110:
1108:
1105:
1104:
1100:
1098:
1096:
1092:
1088:
1082:
1080:
1076:
1072:
1068:
1060:
1058:
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1051:
1049:
1045:
1041:
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1032:
1030:
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1022:
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1010:
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1002:
998:
994:
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978:
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886:
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835:
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827:
823:
818:
814:
810:
802:
800:
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790:
789:methylglyoxal
786:
781:
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777:
769:
767:
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760:
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745:
741:
737:
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721:
715:
713:liver, kidney
712:
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681:liver, kidney
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541:
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90:intermediates
87:
83:
79:
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71:
67:
63:
59:
55:
51:
47:
43:
39:
33:
19:
3143:Chemotherapy
3103:Cell biology
3004:Biochemistry
2928:Neuroscience
2880:
2876:Distribution
2806:Loading dose
2489:Superagonist
2446:Pharmacology
2324:
2305:
2286:
2267:
2251:. Elsevier.
2246:
2216:
2212:
2206:
2181:
2177:
2171:
2160:. Retrieved
2133:
2129:
2119:
2084:
2080:
2070:
2045:
2041:
2035:
2024:. Retrieved
2007:
2003:
1993:
1963:(2): 140–8.
1960:
1956:
1952:
1946:
1911:
1907:
1897:
1852:
1848:
1838:
1785:
1781:
1771:
1736:
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1568:
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1522:
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1511:
1478:
1474:
1434:
1430:
1423:
1412:. Retrieved
1403:
1394:
1361:
1357:
1351:
1326:
1322:
1316:
1292:(2): 291–5.
1289:
1286:Exp. Physiol
1285:
1275:
1240:
1236:
1226:
1193:
1189:
1183:
1172:. Retrieved
1145:
1141:
1094:
1090:
1089:of the book
1083:
1067:benzaldehyde
1064:
1053:
1052:
1035:
1033:
1025:capecitabine
1016:
1012:
989:procainamide
967:
963:
959:
955:
930:
926:polymorphism
921:
894:pathological
893:
889:
887:
878:
870:
864:
836:
829:
806:
773:
756:
744:dipeptidases
725:
536:
485:
446:
444:
430:
377:formaldehyde
366:
358:formaldehyde
350:acetonitrile
346:toxification
339:
301:
281:
273:
244:
240:
217:
205:
173:
125:chemotherapy
109:pharmacology
102:
57:
37:
36:
3228:Bactericide
2904:Compartment
2715:Patch clamp
2691:Schild plot
1575:: 173–219.
1243:(1): 1–11.
1079:sulfonation
1075:acetylation
1071:methylation
985:hydralazine
826:portal vein
793:antioxidant
732:γ-glutamate
677:glutathione
612:acetylation
568:methylation
492:glutathione
453:(to form a
414:peroxidases
373:trimebutine
328:paracetamol
316:cyclization
232:hydrophobic
228:hydrophilic
192:hydrophilic
180:transferase
70:xenobiotics
3285:Toxicology
3280:Hepatology
3275:Metabolism
3269:Categories
3108:Physiology
3040:Toxicology
2932:psychology
2881:Metabolism
2871:Absorption
2865:Liberation
2707:Organ bath
2635:Functional
2514:Antagonist
2507:Inhibitory
2462:Excitatory
2349:Databases
2219:: 741–55.
2162:2012-12-29
2081:Biochem. J
2026:2012-12-29
1855:: 652704.
1614:BioFactors
1414:2017-05-03
1237:Biochem. J
1174:2012-12-29
1118:References
1050:diseases.
1029:irinotecan
993:phenelzine
853:, and the
752:acetylated
590:sulphation
488:conjugated
461:Hydrolysis
369:biomimetic
332:endogenous
312:hydrolysis
209:metabolism
188:lipophilic
169:herbicides
165:pesticides
137:inhibitors
133:substrates
48:by living
2890:Clearance
2886:Excretion
2705:Methods (
2213:Biochem Z
1985:205476485
1928:1752-8054
1871:1664-8021
1812:1932-6203
1054:In silico
981:isoniazid
906:nutrition
871:increases
780:aldehydes
776:peroxides
695:XM-ligase
554:Co-factor
548:Mechanism
510:(-COOH),
467:Esterases
420:Reduction
383:Oxidation
335:substrate
308:reduction
304:oxidation
215:systems.
213:enzymatic
54:enzymatic
50:organisms
3259:Medicine
3008:genetics
2980:Pharmacy
2967:Medicine
2777:Affinity
2736:Efficacy
2674:Analysis
2656:Toxicity
2399:History
2368:SPORCalc
2225:14087340
2198:14625342
2156:Archived
2152:14482007
2111:16748905
2020:Archived
2016:11353742
1977:17268485
1953:in vitro
1937:10818131
1889:33815485
1830:37023111
1821:10079069
1782:PLOS ONE
1763:36658342
1754:10497413
1683:10581368
1634:12897433
1547:23738007
1539:23650932
1495:11593076
1451:19039354
1408:Archived
1386:10698731
1343:11409933
1210:12869659
1168:Archived
1101:See also
956:Phase II
950:than in
937:neonatal
888:Various
879:decrease
748:cysteine
557:Location
542:(GSTs).
252:aldehyde
196:excreted
113:medicine
86:detoxify
2918:Related
2861:(L)ADME
2815:Initial
2799:Metrics
2746:Potency
2729:Metrics
2631:Binding
2601:Binding
2469:Agonist
2405:at the
2102:1205680
2062:6347595
1955:data".
1880:8012690
1790:Bibcode
1711:7568330
1642:7744924
1599:4892500
1503:6068811
1366:Bibcode
1358:Science
1308:9129943
1267:2198020
1258:1131522
1164:2249981
1061:History
948:animals
941:elderly
918:digoxin
851:kidneys
841:of the
811:of the
736:glycine
709:glycine
561:Sources
522:), and
514:(-OH),
512:hydroxy
508:carboxy
500:glycine
496:sulfate
494:(GSH),
471:amidase
352:to HOCH
342:prodrug
298:O + ROH
157:persist
123:and in
40:is the
3245:Portal
2920:fields
2331:
2312:
2293:
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1017:UGT1A1
1009:UGT1A1
1001:CYP3A4
997:CYP2D6
952:adults
944:humans
451:oxygen
129:cancer
78:poison
3117:Other
2854:LADME
1981:S2CID
1914:(2).
1638:S2CID
1543:S2CID
1499:S2CID
1214:S2CID
1048:heart
1046:, or
1040:liver
933:fetal
847:lungs
813:liver
803:Sites
524:thiol
516:amino
502:, or
236:lipid
155:, or
62:xenos
46:drugs
3006:and
2930:and
2766:TD50
2762:LD50
2758:ED50
2754:IC50
2750:EC50
2552:Drug
2329:ISBN
2310:ISBN
2291:ISBN
2272:ISBN
2253:ISBN
2221:PMID
2194:PMID
2148:PMID
2107:PMID
2058:PMID
2012:PMID
1973:PMID
1924:ISSN
1885:PMID
1867:ISSN
1826:PMID
1808:ISSN
1759:PMID
1707:PMID
1679:PMID
1665:1461
1630:PMID
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1585:ISBN
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1447:PMID
1382:PMID
1339:PMID
1304:PMID
1263:PMID
1206:PMID
1160:PMID
1023:and
1021:5-FU
1015:and
1013:DPYD
1005:DPYD
977:NAT2
968:NAT2
946:and
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855:skin
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