Editing Amphetamine (section)

===Pharmacokinetics===
The oral [[bioavailability]] of amphetamine varies with gastrointestinal pH;<ref name="FDA" /> it is well [[Absorption (pharmacology)|absorbed]] from the gut, and bioavailability is typically 90%.<ref name="handbook2022">{{Cite book |title=Handbook of Substance Misuse and Addictions |publisher=Springer International Publishing |year=2022 |isbn=978-3-030-92391-4 |veditors=Patel VB, Preedy VR |location=Cham |page=2006 |doi=10.1007/978-3-030-92392-1 |quote=Amphetamine is usually consumed via inhalation or orally, either in the form of a racemic mixture (levoamphetamine and dextroamphetamine) or dextroamphetamine alone (Childress et al. 2019). In general, all amphetamines have high bioavailability when consumed orally, and in the specific case of amphetamine, 90% of the consumed dose is absorbed in the gastrointestinal tract, with no significant differences in the rate and extent of absorption between the two enantiomers (Carvalho et al. 2012; Childress et al. 2019). The onset of action occurs approximately 30 to 45 minutes after consumption, depending on the ingested dose and on the degree of purity or on the concomitant consumption of certain foods (European Monitoring Centre for Drugs and Drug Addiction 2021a; Steingard et al. 2019). It is described that those substances that promote acidification of the gastrointestinal tract cause a decrease in amphetamine absorption, while gastrointestinal alkalinization may be related to an increase in the compound’s absorption (Markowitz and Patrick 2017).}}</ref> Amphetamine is a weak base with a [[Acid dissociation constant|p''K''<sub>a</sub>]] of 9.9;<ref name="FDA Pharmacokinetics" /> consequently, when the pH is basic, more of the drug is in its [[lipid]] soluble [[free base]] form, and more is absorbed through the lipid-rich [[cell membranes]] of the gut [[epithelium]].<ref name="FDA Pharmacokinetics" /><ref name="FDA" /> Conversely, an acidic pH means the drug is predominantly in a water-soluble [[cation]]ic (salt) form, and less is absorbed.<ref name="FDA Pharmacokinetics" /> Approximately {{nowrap|20%}} of amphetamine circulating in the bloodstream is bound to [[plasma protein]]s.<ref name="Drugbank-amph">{{cite DrugBank|drug=Amphetamine|id=DB00182}}</ref> Following absorption, amphetamine readily [[Distribution (pharmacology)|distributes]] into most tissues in the body, with high concentrations occurring in [[cerebrospinal fluid]] and [[human brain|brain]] tissue.<ref name="HSDB Toxnet October 2017 Full archived record">{{cite encyclopedia |title=Amphetamine |section=Metabolism/Pharmacokinetics |url=http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+300-62-9 |publisher=Hazardous Substances Data Bank. United States National Library of Medicine&nbsp;– Toxicology Data Network |access-date=2 October 2017 |archive-url=https://web.archive.org/web/20171002194327/https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/cgi-bin/sis/search2/f?.%2Ftemp%2F~mdjW95%3A1%3AFULL |archive-date=2 October 2017 |quote=Duration of effect varies depending on agent and urine pH. Excretion is enhanced in more acidic urine. Half-life is 7 to 34&nbsp;hours and is, in part, dependent on urine pH (half-life is longer with alkaline urine).&nbsp;... Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF. Amphetamine appears in the urine within about 3&nbsp;hours following oral administration.&nbsp;... Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine}}</ref>

The [[Biological half-life|half-lives]] of amphetamine enantiomers differ and vary with urine pH.<ref name="FDA Pharmacokinetics" /> At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are {{nowrap|9–11}}&nbsp;hours and {{nowrap|11–14}}&nbsp;hours, respectively.<ref name="FDA Pharmacokinetics" /> Highly acidic urine will reduce the enantiomer half-lives to 7&nbsp;hours;<ref name="HSDB Toxnet October 2017 Full archived record" /> highly alkaline urine will increase the half-lives up to 34&nbsp;hours.<ref name="HSDB Toxnet October 2017 Full archived record" /> The immediate-release and extended release variants of salts of both isomers reach [[Cmax (pharmacology)|peak plasma concentrations]] at 3&nbsp;hours and 7&nbsp;hours post-dose respectively.<ref name="FDA Pharmacokinetics" /> Amphetamine is [[Elimination (pharmacology)|eliminated]] via the [[kidney]]s, with {{nowrap|30–40%}} of the drug being excreted unchanged at normal urinary pH.<ref name="FDA Pharmacokinetics" /> When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.<ref name="FDA Pharmacokinetics" /> When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.<ref name="FDA Pharmacokinetics" /> Following oral administration, amphetamine appears in urine within 3&nbsp;hours.<ref name="HSDB Toxnet October 2017 Full archived record" /> Roughly 90% of ingested amphetamine is eliminated 3&nbsp;days after the last oral dose.<ref name="HSDB Toxnet October 2017 Full archived record" />{{if pagename|Adderall=|Dextroamphetamine=|other=&nbsp;

Lisdexamfetamine is a [[prodrug]] of dextroamphetamine.<ref name="pmid27021968" /><ref name=USVyvanselabel /> It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract.<ref name=USVyvanselabel>{{cite web | title=Vyvanse- lisdexamfetamine dimesylate capsule Vyvanse- lisdexamfetamine dimesylate tablet, chewable | website=DailyMed | publisher = Shire US Inc. | date=30 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=704e4378-ca83-445c-8b45-3cfa51c1ecad | access-date=22 December 2019}}</ref> Following absorption into the blood stream, lisdexamfetamine is completely converted by [[red blood cell]]s to dextroamphetamine and the [[amino acid]] [[lysine|<small>L</small>-lysine]] by [[hydrolysis]] via undetermined [[aminopeptidase]] [[enzyme]]s.<ref name=USVyvanselabel/><ref name="pmid27021968" /><ref name="pmid28936175">{{cite journal | vauthors = Dolder PC, Strajhar P, Vizeli P, Hammann F, Odermatt A, Liechti ME | title = Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects | journal = Front Pharmacol | volume = 8 | issue = | pages = 617 | date = 2017 | pmid = 28936175 | pmc = 5594082 | doi = 10.3389/fphar.2017.00617 | quote = Inactive lisdexamfetamine is completely (>98%) converted to its active metabolite D-amphetamine in the circulation (Pennick, 2010; Sharman and Pennick, 2014). When lisdexamfetamine is misused intranasally or intravenously, the pharmacokinetics are similar to oral use (Jasinski and Krishnan, 2009b; Ermer et al., 2011), and the subjective effects are not enhanced by parenteral administration in contrast to D-amphetamine (Lile et al., 2011) thus reducing the risk of parenteral misuse of lisdexamfetamine compared with D-amphetamine. Intravenous lisdexamfetamine use also produced significantly lower increases in "drug liking" and "stimulant effects" compared with D-amphetamine in intravenous substance users (Jasinski and Krishnan, 2009a).| doi-access = free | title-link = doi }}</ref> This is the [[rate-limiting step]] in the [[bioactivation]] of lisdexamfetamine.<ref name="pmid27021968" /> The elimination half-life of lisdexamfetamine is generally less than 1&nbsp;hour.<ref name=USVyvanselabel /><ref name="pmid27021968" /> Due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine.<ref name="pmid27021968">{{cite journal | vauthors = Ermer JC, Pennick M, Frick G | title = Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy | journal = Clinical Drug Investigation | volume = 36 | issue = 5 | pages = 341–356 | date = May 2016 | pmid = 27021968 | pmc = 4823324 | doi = 10.1007/s40261-015-0354-y }}</ref><ref name="pmid28936175" /> Presumably due to its rate-limited activation by red blood cells, [[intravenous administration]] of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine.<ref name="pmid27021968" /> The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally, [[intranasal administration|intranasally]], or intravenously.<ref name="pmid27021968" /><ref name="pmid28936175" /> Hence, in contrast to dextroamphetamine, [[parenteral administration|parenteral]] use does not enhance the subjective effects of lisdexamfetamine.<ref name="pmid27021968" /><ref name="pmid28936175" /> Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.<ref name="pmid27021968" /><ref name="pmid28936175" />
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[[CYP2D6]], [[dopamine β-hydroxylase]] (DBH), [[flavin-containing monooxygenase 3]] (FMO3), [[butyrate-CoA ligase]] (XM-ligase), and [[glycine N-acyltransferase|glycine ''N''-acyltransferase]] (GLYAT) are the enzymes known to [[Drug metabolism|metabolize]] amphetamine or its metabolites in humans.<ref name="amphetamine metabolism" group = "sources" /> Amphetamine has a variety of excreted metabolic products, including {{nowrap|[[4-hydroxyamphetamine]]}}, {{nowrap|[[4-hydroxynorephedrine]]}}, {{nowrap|[[4-hydroxyphenylacetone]]}}, [[benzoic acid]], [[hippuric acid]], [[norephedrine]], and [[phenylacetone]].<ref name="FDA Pharmacokinetics" /><ref name="Metabolites" /> Among these metabolites, the active [[sympathomimetics]] are {{nowrap|4-hydroxyamphetamine}},<ref>{{cite encyclopedia |title=p-Hydroxyamphetamine. PubChem Compound Database|section-url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3651 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information | access-date=15 October 2013 |section=Compound Summary}}</ref> {{nowrap|4-hydroxynorephedrine}},<ref>{{cite encyclopedia |title=p-Hydroxynorephedrine. PubChem Compound Database |section-url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11099 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information |access-date=15 October 2013 |section=Compound Summary}}</ref> and norephedrine.<ref>{{cite encyclopedia |title=Phenylpropanolamine. PubChem Compound Database |section-url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=26934 |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information |access-date=15 October 2013 |section=Compound Summary}}</ref> The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, ''N''-oxidation, ''N''-dealkylation, and deamination.<ref name="FDA Pharmacokinetics" /><ref name="Pubchem Kinetics">{{cite encyclopedia |title=Amphetamine. Pubchem Compound Database |section-url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007#section=Pharmacology-and-Biochemistry |publisher=United States National Library of Medicine&nbsp;– National Center for Biotechnology Information |access-date=12 October 2013 |section=Pharmacology and Biochemistry}}</ref> The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:
{{Amphetamine pharmacokinetics|caption=The primary active metabolites of amphetamine are {{nowrap|4-hydroxyamphetamine}} and norephedrine;<ref name="Metabolites" /> at normal urine pH, about {{nowrap|30–40%}} of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).<ref name="FDA Pharmacokinetics" /> The remaining {{nowrap|10–20%}} is excreted as the active metabolites.<ref name="FDA Pharmacokinetics" /> Benzoic acid is metabolized by {{abbr|XM-ligase|butyrate-CoA ligase}} into an intermediate product, [[benzoyl-CoA]], which is then metabolized by {{abbr|GLYAT|glycine ''N''-acyltransferase}} into hippuric acid.<ref name="Glycine conjugation review" />}}
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