View source for Template:Amphetamine pharmacokinetics

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| header = {{{header|Metabolic pathways of amphetamine in humans{{#tag:ref|<ref name="FDA Pharmacokinetics">{{cite web | title = Adderall XR Prescribing Information | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf | pages = 12–13 | publisher = Shire US Inc | work = United States Food and Drug Administration |date=December 2013 | accessdate = 30 December 2013 }}</ref><ref name="Substituted amphetamines, FMO, and DBH">{{cite book | author = Glennon RA |veditors=Lemke TL, Williams DA, Roche VF, Zito W | title=Foye's principles of medicinal chemistry | date=2013 | publisher=Wolters Kluwer Health/Lippincott Williams & Wilkins | location=Philadelphia, USA | isbn=9781609133450 | pages=646–648 | edition=7th | section-url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646 | section=Phenylisopropylamine stimulants: amphetamine-related agents | quote=The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).&nbsp;... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase.&nbsp;... Amphetamine can also undergo aromatic hydroxylation to ''p''-hydroxyamphetamine.&nbsp;... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords ''p''-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.}}</ref><ref name="DBH amph primary">{{cite journal | author = Taylor KB | title = Dopamine-beta-hydroxylase. Stereochemical course of the reaction | journal = Journal of Biological Chemistry | volume = 249 | issue = 2 | pages = 454–458 | date = January 1974 | pmid = 4809526 | accessdate = 6 November 2014 | url = http://www.jbc.org/content/249/2/454.full.pdf | quote = Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine. }}</ref><ref name="FMO">{{cite journal |vauthors=Krueger SK, Williams DE | title = Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism | journal = Pharmacology & Therapeutics | volume = 106 | issue = 3 | pages = 357–387 |date=June 2005 | pmid = 15922018 | pmc = 1828602 | doi = 10.1016/j.pharmthera.2005.01.001}}<br />[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602/table/T5/ Table 5: N-containing drugs and xenobiotics oxygenated by FMO]</ref><ref name="FMO3-Primary">{{cite journal |vauthors=Cashman JR, Xiong YN, Xu L, Janowsky A | title = N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication | journal = Journal of Pharmacology and Experimental Therapeutics | volume = 288 | issue = 3 | pages = 1251–1260 | date = March 1999 |pmid = 10027866 }}</ref><ref name="Metabolites">{{cite journal |vauthors=Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G | title = Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 30 | issue = 2 | pages = 247–255 |date=September 2002 | pmid = 12191709 | doi =10.1016/S0731-7085(02)00330-8 }}</ref><ref name="pmid13977820">{{cite journal | vauthors = Sjoerdsma A, von Studnitz W | title = Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate | journal = British Journal of Pharmacology and Chemotherapy | volume = 20 | issue = | pages = 278–284 | date = April 1963 | pmid = 13977820 | pmc = 1703637 | doi = 10.1111/j.1476-5381.1963.tb01467.x| quote = Hydroxyamphetamine was administered orally to five human subjects&nbsp;... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man.&nbsp;... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues.&nbsp;... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.}}</ref><ref name="Glycine conjugation review">{{cite journal | vauthors = Badenhorst CP, van der Sluis R, Erasmus E, van Dijk AA | title = Glycine conjugation: importance in metabolism, the role of glycine N-acyltransferase, and factors that influence interindividual variation | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 9 | issue = 9 | pages = 1139–1153 | date = September 2013 | pmid = 23650932 | doi = 10.1517/17425255.2013.796929 | quote = 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.&nbsp;... 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. }}</ref>| name="amphetamine metabolism" |group = "sources" }}}}}
| header_align = center
| header_background = aliceblue
| alt = Graphic of several routes of amphetamine metabolism
| image = Amph Pathway.png
| image-width = 700
| image-left = -10
| image-top = 3
| align = {{{align|center}}}
| width = 685
| height = 375
| annot-font-size = 16
| annot-text-align = center
| annotations =

{{Annotation|2|350|[[Chemistry:4-Hydroxyphenylacetone|4-Hydroxyphenylacetone]]}}
{{Annotation|210|350|[[Chemistry:Phenylacetone|Phenylacetone]]}}
{{Annotation|380|350|[[Chemistry:Benzoic acid|Benzoic acid]]}}
{{Annotation|560|350|[[Chemistry:Hippuric acid|Hippuric acid]]}}

{{Annotation|45|220|{{if pagename |Amphetamine=Amphetamine |other=[[Chemistry:Amphetamine|Amphetamine]]}} }}
{{Annotation|300|220|[[Chemistry:Phenylpropanolamine|Norephedrine]]}}

{{Annotation|255|90|[[Chemistry:4-Hydroxyamphetamine|4-Hydroxyamphetamine]]}}
{{Annotation|490|90|[[Chemistry:P-Hydroxynorephedrine|4-Hydroxynorephedrine]]}}

{{annotation|145|115|Para-<br/>Hydroxylation|font-size=10}}
{{annotation|384|115|Para-<br/>Hydroxylation|font-size=10}}
{{annotation|150|294|Para-<br/>Hydroxylation|font-size=10}}
{{annotation|151|138|[[Biology:CYP2D6|CYP2D6]]|font-size=12}}
{{annotation|390|138|[[Biology:CYP2D6|CYP2D6]]|font-size=12}}
{{annotation|150|330|unidentified|font-size=12}}

{{annotation|190|165|Beta-<br/>Hydroxylation|font-size=10}}
{{annotation|415|25|Beta-<br/>Hydroxylation|font-size=10}}
{{annotation|206|195|[[Biology:Dopamine beta-hydroxylase|DBH]]|font-size=12}}
{{annotation|428|55|[[Biology:Dopamine beta-hydroxylase|DBH]]<br />{{#tag:ref|{{nowrap|4-Hydroxyamphetamine}} has been shown to be metabolized into {{nowrap|4-hydroxynorephedrine}} by dopamine beta-hydroxylase (DBH) ''[[In vitro|in vitro]]'' and it is presumed to be metabolized similarly ''[[Biology:In vivo|in vivo]]''.<ref name="Substituted amphetamines, FMO, and DBH" /><ref name="pmid13977820" /> Evidence from studies that measured the effect of serum DBH concentrations on {{nowrap|4-hydroxyamphetamine}} metabolism in humans suggests that a different enzyme may mediate the conversion of {{nowrap|4-hydroxyamphetamine}} to {{nowrap|4-hydroxynorephedrine}};<ref name="pmid13977820" /><ref name="DBH 4-HA primary">{{cite journal |vauthors=Horwitz D, Alexander RW, Lovenberg W, Keiser HR | title = Human serum dopamine-β-hydroxylase. Relationship to hypertension and sympathetic activity | journal =Circulation Research | volume = 32 | issue = 5 | pages = 594–599 | date = May 1973 | pmid = 4713201 | doi = 10.1161/01.RES.32.5.594 | quote = The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity.&nbsp;... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).}}</ref> however, other evidence from animal studies suggests that this reaction is catalyzed by DBH in [[Biology:Synaptic vesicle|synaptic vesicle]]s within noradrenergic neurons in the brain.<ref name="pmid4457764">{{cite journal | vauthors = Freeman JJ, Sulser F | title = Formation of p-hydroxynorephedrine in brain following intraventricular administration of p-hydroxyamphetamine | journal = Neuropharmacology | volume = 13 | issue = 12 | pages = 1187–1190 | date = December 1974 | pmid = 4457764 | doi = 10.1016/0028-3908(74)90069-0 | quote = In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, ''p''-hydroxyamphetamine (POH) and ''p''-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug.&nbsp;... The location of the ''p''-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.<br />The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.}}</ref><ref name="pmid2600821">{{cite journal | vauthors = Matsuda LA, Hanson GR, Gibb JW | title = Neurochemical effects of amphetamine metabolites on central dopaminergic and serotonergic systems | journal = Journal of Pharmacology and Experimental Therapeutics | volume = 251 | issue = 3 | pages = 901–908 | date = December 1989 | pmid = 2600821 | doi = | quote = The metabolism of ''p''-OHA to ''p''-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert ''p''-OHA to ''p''-OHNor after intraventricular administration.}}</ref>|group="note"}}|font-size=12}}

{{annotation|210|220|Oxidative<br/>Deamination|font-size=10}}
{{annotation|220|242|[[Biology:Flavin-containing monooxygenase 3|FMO3]]|font-size=12}}

{{annotation|330|307|Oxidation|font-size=10}}
{{annotation|323|330|unidentified|font-size=12}}
{{annotation|478|293|Glycine<br/>Conjugation|font-size=10}}
{{annotation|480|330|[[Biology:Butyrate—CoA ligase|XM-ligase]]<br />[[Biology:Glycine N-acyltransferase|GLYAT]]|font-size=12}}

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