The Journey of Aspirin

Aspirin (acetylsalicylic acid, ASA) is absorbed rapidly from the
gastrointestinal tract, primarily in the stomach and upper small intestine. Its pKa of 3.5 means
that in the acidic gastric environment (pH 1-2), the molecule is largely un-ionized and therefore
lipophilic enough to permeate gastric mucosa directly. Absorption is essentially complete within
30-40 minutes of an oral dose. Enteric-coated formulations delay absorption to the small intestine,
smoothing peak plasma concentrations and reducing gastric mucosal damage at the cost of delayed
onset. Food slows but does not prevent absorption. Bioavailability of immediate-release aspirin is
approximately 50-75% because first-pass hydrolysis in the gut wall and liver converts a substantial
fraction to salicylate before it reaches the systemic circulation. This presystemic deacetylation
is pharmacologically significant: aspirin itself is the active acetylating species, while salicylate
is a weaker, non-acetylating analgesic/anti-inflammatory agent.

Once absorbed, aspirin undergoes rapid hydrolysis by plasma
esterases (principally butyrylcholinesterase) and hepatic esterases to form salicylate, which then
distributes widely. Salicylate is 80-90% bound to plasma albumin at therapeutic concentrations,
though binding becomes saturated at higher doses, increasing the free fraction and toxicity risk.
The volume of distribution of salicylate is approximately 0.1-0.3 L/kg at low doses. Salicylate
penetrates most body compartments including the CNS, synovial fluid, and breast milk. It crosses
the placenta readily. The brain concentration is lower than plasma due to active efflux, but at
toxic doses CNS accumulation causes tinnitus, confusion, and respiratory alkalosis followed by
metabolic acidosis. Aspirin itself (the intact acetyl compound) has a plasma half-life of only
15-20 minutes before hydrolysis to salicylate.

Aspirin's defining pharmacological action is irreversible inhibition
of cyclooxygenase (COX) enzymes — both COX-1 and COX-2 — via covalent acetylation of a serine
residue (Ser530 on COX-1, Ser516 on COX-2). This acetylation blocks the hydrophobic channel
through which arachidonic acid accesses the catalytic site, permanently inactivating the enzyme.
Because platelets are anucleate and cannot synthesize new COX-1, a single aspirin dose (as low
as 75 mg) abolishes thromboxane A₂-dependent platelet aggregation for the platelet's entire
7-10 day lifespan. This forms the mechanistic basis of aspirin's antiplatelet therapy for
cardiovascular prevention. At higher doses (500 mg-4 g/day), aspirin inhibits endothelial
prostacyclin (PGI₂) synthesis and reduces prostaglandin E₂ and F₂α production in peripheral
tissues, conferring analgesic, antipyretic, and anti-inflammatory effects. Antipyresis results from
blocking prostaglandin-mediated resetting of the hypothalamic thermostat. The COX-1/COX-2
selectivity ratio differs: aspirin is approximately 166-fold more potent against COX-1 than COX-2
at inhibiting arachidonic acid oxygenation.

The primary metabolic pathway for salicylate is conjugation with
glycine in the liver to form salicyluric acid (75% at low doses), and to a lesser extent
glucuronide conjugation at the carboxyl (ether glucuronide, ~10%) and phenolic hydroxyl groups
(ester glucuronide, ~5%). A small fraction undergoes hydroxylation to gentisic acid (2,5-
dihydroxybenzoic acid). Critically, the glycine conjugation pathway saturates at therapeutic doses
because hepatic glycine supply is rate-limiting, converting aspirin's kinetics from first-order
(at low doses) to zero-order (at high anti-inflammatory doses). This saturable metabolism means
small increases in dose produce disproportionately large increases in plasma salicylate
concentration — the Michaelis-Menten kinetics that make high-dose aspirin therapy hazardous and
require plasma level monitoring. The elimination half-life of salicylate increases from 2-3 hours
at analgesic doses to 15-30 hours at anti-inflammatory doses.

Salicylate and its metabolites are excreted by the kidneys. Renal
clearance is pH-dependent: alkaline urine (pH > 7) dramatically increases ionization of salicylate
(pKa 3.0), trapping it in tubular fluid and preventing reabsorption, thereby accelerating
elimination up to 3-5-fold. This principle underpins urinary alkalinization with sodium bicarbonate
as a treatment for salicylate overdose. Conversely, acidic urine (as in dehydration or metabolic
acidosis) markedly reduces renal clearance and worsens toxicity.

Aspirin's irreversible antiplatelet effect at low doses (75-325 mg/day)
reduces cardiovascular events in secondary prevention by 25%. Its use requires balancing
gastrointestinal bleeding risk (increased 2-4-fold) against ischemic benefit. Drug interactions
include displacement of warfarin from albumin (increasing free anticoagulant), inhibition of
uricosuric effects of probenecid at intermediate doses, and antagonism of antihypertensive drugs
at high doses via prostaglandin-mediated sodium retention. Reye's syndrome risk in viral
infections in children under 16 restricts aspirin use in pediatric febrile illness.