Editing Aspirin (section)

==Pharmacokinetics==
Acetylsalicylic acid is a [[weak acid]], and very little of it is [[Acid dissociation constant|ionized]] in the [[stomach]] after oral administration. Acetylsalicylic acid is quickly absorbed through the cell membrane in the [[acidic]] conditions of the stomach. The higher [[pH]] and larger surface area of the [[small intestine]] cause aspirin to be absorbed more slowly there, as more of it is ionized. Owing to the formation of concretions, aspirin is absorbed much more slowly during overdose, and [[blood plasma]] concentrations can continue to rise for up to 24 hours after ingestion.<ref name="RK Ferguson">{{cite journal | vauthors = Ferguson RK, Boutros AR | title = Death following self-poisoning with aspirin | journal = JAMA | volume = 213 | issue = 7 | pages = 1186–8 | date = August 1970 | pmid = 5468267 | doi = 10.1001/jama.213.7.1186 }}</ref><ref name="FL Kaufman">{{cite journal | vauthors = Kaufman FL, Dubansky AS | title = Darvon poisoning with delayed salicylism: a case report | journal = Pediatrics | volume = 49 | issue = 4 | pages = 610–1 | date = April 1972 | doi = 10.1542/peds.49.4.610 | pmid = 5013423 | s2cid = 29427204 }}</ref><ref name="G Levy">{{cite journal | vauthors = Levy G, Tsuchiya T | title = Salicylate accumulation kinetics in man | journal = The New England Journal of Medicine | volume = 287 | issue = 9 | pages = 430–2 | date = August 1972 | pmid = 5044917 | doi = 10.1056/NEJM197208312870903 }}</ref>

About 50–80% of salicylate in the blood is bound to [[human serum albumin]], while the rest remains in the active, ionized state; protein binding is concentration-dependent. Saturation of binding sites leads to more free salicylate and increased toxicity. The volume of distribution is 0.1–0.2 L/kg. Acidosis increases the volume of distribution because of enhancement of tissue penetration of salicylates.<ref name="G Levy"/>

As much as 80% of therapeutic doses of salicylic acid is [[metabolism|metabolized]] in the [[liver]]. [[Conjugated system|Conjugation]] with [[glycine]] forms [[salicyluric acid]], and with [[glucuronic acid]] to form two different glucuronide esters. The conjugate with the acetyl group intact is referred to as the ''acyl glucuronide''; the deacetylated conjugate is the ''phenolic glucuronide''. These metabolic pathways have only a limited capacity. Small amounts of salicylic acid are also hydroxylated to [[gentisic acid]]. With large salicylate doses, the kinetics switch from first-order to zero-order, as [[metabolic pathway]]s become saturated and [[kidney|renal]] excretion becomes increasingly important.<ref name="G Levy"/>

Salicylates are excreted mainly by the kidneys as salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%), acyl glucuronides (5%), [[gentisic acid]] (< 1%), and [[2,3-Dihydroxybenzoic acid|2,3-dihydroxybenzoic acid]].<ref name="pmid3342084">{{cite journal | vauthors = Grootveld M, Halliwell B | title = 2,3-Dihydroxybenzoic acid is a product of human aspirin metabolism | journal = Biochemical Pharmacology | volume = 37 | issue = 2 | pages = 271–80 | date = January 1988 | pmid = 3342084 | doi = 10.1016/0006-2952(88)90729-0 }}</ref> When small doses (less than 250{{nbsp}}mg in an adult) are ingested, all pathways proceed by first-order kinetics, with an elimination half-life of about 2.0 h to 4.5 h.<ref name="O Hartwig">{{cite journal | vauthors = Hartwig-Otto H | title = Pharmacokinetic considerations of common analgesics and antipyretics | journal = The American Journal of Medicine | volume = 75 | issue = 5A | pages = 30–7 | date = November 1983 | pmid = 6606362 | doi = 10.1016/0002-9343(83)90230-9 }}</ref><ref name="AK Done">{{cite journal | vauthors = Done AK | title = Salicylate intoxication. Significance of measurements of salicylate in blood in cases of acute ingestion | journal = Pediatrics | volume = 26 | pages = 800–7 | date = November 1960 | doi = 10.1542/peds.26.5.800 | pmid = 13723722 | s2cid = 245036862 }}</ref> When higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer (15 h to 30 h),<ref name="Chyka2007">{{cite journal | vauthors = Chyka PA, Erdman AR, Christianson G, Wax PM, Booze LL, Manoguerra AS, Caravati EM, Nelson LS, Olson KR, Cobaugh DJ, Scharman EJ, Woolf AD, Troutman WG | title = Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management | journal = Clinical Toxicology | volume = 45 | issue = 2 | pages = 95–131 | year = 2007 | pmid = 17364628 | doi = 10.1080/15563650600907140 | doi-access = free | title-link = doi }}</ref> because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide become saturated.<ref>{{cite journal | vauthors = Prescott LF, Balali-Mood M, Critchley JA, Johnstone AF, Proudfoot AT | title = Diuresis or urinary alkalinisation for salicylate poisoning? | journal = British Medical Journal | volume = 285 | issue = 6352 | pages = 1383–6 | date = November 1982 | pmid = 6291695 | pmc = 1500395 | doi = 10.1136/bmj.285.6352.1383 }}</ref> Renal excretion of salicylic acid becomes increasingly important as the metabolic pathways become saturated, because it is extremely sensitive to changes in [[urine|urinary]] pH. A 10- to 20-fold increase in renal clearance occurs when urine pH is increased from 5 to 8. The use of urinary alkalinization exploits this particular aspect of salicylate elimination.<ref name="EmergMed2002-Dargan">{{cite journal | vauthors = Dargan PI, Wallace CI, Jones AL | title = An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose | journal = Emergency Medicine Journal | volume = 19 | issue = 3 | pages = 206–9 | date = May 2002 | pmid = 11971828 | pmc = 1725844 | doi = 10.1136/emj.19.3.206 }}</ref> It was found that short-term aspirin use in therapeutic doses might precipitate reversible [[acute kidney injury]] when the patient was ill with [[glomerulonephritis]] or [[cirrhosis]].<ref name=amjkid/> Aspirin for some patients with [[chronic kidney disease]] and some children with congestive heart failure was contraindicated.<ref name=amjkid>{{cite journal | vauthors = D'Agati V | title = Does aspirin cause acute or chronic renal failure in experimental animals and in humans? | journal = American Journal of Kidney Diseases | volume = 28 | issue = 1 Suppl 1 | pages = S24-9 | date = July 1996 | pmid = 8669425 | doi = 10.1016/s0272-6386(96)90565-x }}</ref>