Synonyms. Acetaminophen; N-Acetyl–p–aminophenol.

Proprietary names. Paracetamol is an ingredient of many proprietary preparations—see

Martindale, The complete drug reference, 33rd Edn., Pharmaceutical Press, London, 2002.

N-(4-Hydroxyphenyl)acetamide

C8H9NO2=151.2

CAS—103–90–2

White crystals or crystalline powder. M.p. 169.0° to 170.5° (from water).

Very slightly soluble in cold water, considerably more soluble in hot water; soluble in ethanol,
methanol, dimethylformamide, ethylene dichloride, acetone, and ethyl acetate; very slightly
soluble in chloroform; slightly soluble in ether; practically insoluble in petroleum ether, pentane,
and benzene.

Dissociation Constant.
pKa 9.5 (25°).

Partition Coefficient.
Log P(octanol/water), 0.5.

Colour Tests.
Ferric Chloride—blue; Folin–Ciocalteu Reagent—blue; Liebermann's Test—violet; Nessler's
Reagent—brown (slow).

Boil 0.1 g with 1 mL of hydrochloric acid for 3 min, add 10 mL of water, cool, and add 0.05 mL
of 0.02 M potassium dichromate—violet, developing slowly (which in contrast to phenacetin
does not become red).

Thin–layer Chromatography.
System TA—Rf 95; system TB—Rf 00; system TD—Rf 15; system TE—Rf 45; system TF—Rf
32; system TAD—Rf 26; system TAE—Rf 77; system TAJ—Rf 30; system TAK—Rf 05;
system TAL—Rf 73. (Ferric chloride solution, faint blue; acidified potassium permanganate
solution, positive.)

Gas Chromatography.
System GA—paracetamol RI 1665, art (p-aminophenol) RI 1253, paracetamol-Me RI 1512, art
(p-aminophenol)-Me2 RI 1220; system GB—paracetamol RI 1722, art (p-aminophenol) RI 1280;
system GL—paracetamol-Me RI 1630.

High Performance Liquid Chromatography.

System HD—k 0.1; system HW—k 0.32; system HX—RI 264; system HY—RI 241; system
HZ—retention time 1.9 min; system HAA—retention time 5.6 min; system HAM—retention
time 2.0 min; system HAX—retention time 4.8 min; system HAY—retention time 3.7 min.

Ultraviolet Spectrum.
Aqueous acid—245 (A11=668a); aqueous alkali—257 nm (A11=715a).

Infra–red Spectrum.
Principal peaks at wavenumbers 1506, 1657, 1565, 1263, 1227, 1612 cm−1 (KBr disk). (See
below)

Mass Spectrum.
Principal ions at m/z 109, 151, 43, 80, 108, 81, 53, 52; cysteine conjugate 141, 43, 183, 44, 140,
80, 108, 52; mercapturic acid conjugate 43, 141, 183, 42, 87, 41, 140, 165.

Quantification
Gas chromatography.

In serum: limit of detection 7.5 mg/L, FID—E. Kaa,J. Chromatogr.,1980, 221(10) B Biomed.
Appl., 414–418.
Gas chromatography–mass spectrometry.

In whole blood or liver—J. Speed et al.,J. Anal. Toxicol.,2001, 25, 198–202.

High performance liquid chromatography.

In plasma: limit of detection 50 μg/L, UV detection—J. N. Buskin et al.,J. Chromatogr.,1982,

230(19) B Biomed. Appl., 443–447. In urine: paracetamol and 7 metabolites, electrochemical
and UV detection—J. M. Wilson et al.,J. Chromatogr.,1982, 227(16) B Biomed. Appl., 453–
462. In blood or postmortem tissues: UV detection—J. C. West,J. Anal. Toxicol.,1981, 5, 118–
121. In blood or plasma: limit of detection 0.1 mg/L, electrochemical detection—R. Whelpton et
al.,Biomed. Chromatogr.,1993, 7, 90–93. In plasma or urine: paracetamol and its major
metabolites, UV detection—G. S. Lau and J. A. Critchley,J. Pharm. Biomed. Anal.,1994, 12,
1563–1572. In plasma, urine, or saliva—S. S. al-Obaidy et al.,J. Pharm. Biomed. Anal.,1995, 13,
1033–1039. In urine: paracetamol and its glucuronide and sulfate metabolites, UV detection—A.
Di Girolamo et al.,J. Pharm. Biomed. Anal.,1998, 17, 1191–1197. In blood, urine, CSF, synovial
fluid, vitreous humour, or tissue samples: UV detection—E. Pufal et al.,Fresenius J. Anal.
Chem.,2000, 367, 596–599. In serum: paracetamol–protein adducts, electrochemical detection—
K. L. Muldrew et al.,Drug Metab. Dispos.,2002, 30, 446–451. In blood (on spot card): limit of
detection 600 pg, UV detection—E. J. Oliveira et al.,J. Pharm. Biomed. Anal.,2002, 29, 803–
809.

Disposition in the Body.

Small doses are readily absorbed but the absorption of larger doses varies considerably and is
influenced by gastric emptying rate, the presence of food, and the time of day. Paracetamol is
widely distributed throughout most body fluids and is present in the saliva at concentrations
paralleling those in plasma. It crosses the placenta and is found in breast milk. It undergoes first–
pass metabolism and is metabolised mainly by conjugation to form glucuronides and ethereal
sulfates; 3–hydroxylation also occurs followed by conjugation or O-methylation of the hydroxy
group. Oxidation to a reactive metabolite thought to be acetylimino–p–benzoquinone occurs to a
small extent after therapeutic doses but becomes more significant after larger doses, and this
metabolite appears to be responsible for hepatic necrosis in paracetamol overdosage; it is
normally detoxified by glutathione conjugation to form mercapturic acid and cysteine conjugates
but, once sources of glutathione are depleted, the free metabolite is available to bind covalently
with liver cell protein; this binding occurs about 10 to 12 h after dosing. About 90% of a
therapeutic dose is excreted in the urine in 24 h; of the excreted material, 1 to 4% is unchanged,
20 to 30% is conjugated with sulfate, 40 to 60% is conjugated with glucuronic acid, 5 to 10%
consists of the 3–hydroxy–3–sulfate, the 3–methoxyglucuronide, and the 3–methoxy–3–sulfate
metabolites, and about 5 to 10% consists of the mercapturic acid and cysteine conjugates; 3–
methylthio–4–hydroxyacetanilide has also been identified at concentrations of less than 1%.
Larger amounts of the mercapturic acid and cysteine conjugates are excreted in overdose.

Paracetamol is a metabolite of benorilate and phenacetin.

Therapeutic concentration.
In plasma, usually in the range 10 to 20 mg/L. Plasma concentrations vary considerably between
subjects. The glucuronide and sulfate conjugates accumulate in subjects with impaired renal
function.

After a single oral dose of 1.5 g to 14 subjects, peak plasma paracetamol concentrations of 7.4 to
37 mg/L (mean 24) were attained in 0.5 to 3 h (mean 1.4). [R. C. Heading et al.,Br. J.
Pharmacol.,1973, 47, 415–421.]

Of 24 children (over 25 kg) undergoing elective surgery, given paracetamol rectally at a dose of
1 or 40 mg/kg, most children in the 1–g group failed to attain therapeutic plasma levels whereas
those in the 40 mg/kg group did (mean peak plasma concentration 7.8 vs 15.9 mg/L attained at
3.8 and 2.6 h, respectively). [T. K. Howell and D. Patel,Anaesthesia,2003, 58, 69–73.]

Following administration of 4 rectal doses of paracetamol, 20 mg/kg every 6 h, to 10 term

neonates undergoing painful procedures or having painful conditions, mean peak serum
concentrations were 10.79, 15.34, and 6.24 mg/L in the whole group, boys, and girls,
respectively; the median time to peak serum concentration was 1.5 h after the first dose and 15 h
for multiple doses. A starting dose of 30 mg/kg followed by 20 mg/kg rectally at intervals
increasing from 6 to 8 h was proposed for neonates. [R. A. van Lingen et al.,Clin. Pharmacol.
Ther.,1999, 66, 509–515.]

Toxicity.

The minimum lethal dose is about 10 g. Symptoms of hepatic damage do not occur for at least
12 h after overdosage but may not appear until 4 to 6 days later. Plasma concentrations have
been used to indicate possible hepatic necrosis; at 4 h, hepatic necrosis is possible at
concentrations of paracetamol of 120 to 300 mg/L, probable at concentrations above 300 mg/L,
and unlikely at concentrations below 120 mg/L. Similarly, at 12 h, concentrations above
120 mg/L indicate the probability of necrosis, concentrations of 50 to 120 mg/L indicate that it is
possible, and concentrations below 50 mg/L indicate that it is unlikely.

Of 93 patients hospitalised for paracetamol toxicity, 80 were classified as suicidal and 13 had
accidentally poisoned themselves in an attempt to relieve pain. Peak plasma levels were higher in
the suicidal overdose group (mean 121.7 mg/L) than in the accidental overdose group
(64.5 mg/L). [G. G. GyamLani and C. R. Parikh,Crit. Care,2002, 6, 155–159.]

A 6–year–old child died after receiving paracetamol overdosage over a period of 3 days. The
prescribed dose for fever (associated with measles) had been 325 mg every 6 h, but the child’s
mother, believing paracetamol to be non–toxic, had progressively increased the dose firstly in
response to the fever and subsequently for abdominal pain (500 mg every 4 h for 48 h followed
by 500 mg every 2 to 3 h for 12 h had been given). On admission to hospital 11 h after the last
dose, the child’s serum paracetamol concentration was 163 mg/L. Despite appropriate treatment,
the child died on the 11th day. [K. V. Blake et al.,Clin. Pharm.,1988, 7, 391–397.]
The following postmortem tissue concentrations were reported in 3 fatalities: blood 160, 200,
and 387 mg/L, bile 180, -, 900 mg/L, liver -, -, 385 μg/g, liver blood 200, -, 475 mg/L, urine 180,
620, - mg/L. [A. E. Robinson et al.,J. Forensic Sci.,1977, 22, 708–717.]

Bioavailability.

70 to 90%.

Half–life.

Plasma half–life after therapeutic doses, adults about 1 to 3 h, neonates, about 5 h; plasma half–
lives greater than about 4 h in adults are indicative of possible liver damage.

Volume of distribution.

About 1 L/kg.

Clearance.

Plasma clearance, about 5 mL/min/kg.

Protein binding.

In plasma, not bound at concentrations less than 60 mg/L. In poisoned subjects, protein binding
has been reported to vary between about 8% and 40%.

Note.

For a review of the pharmacokinetics of paracetamol, see J. A. H. Forrest et al.,Clin.

Pharmacokinet.,1982, 7, 93–107. For a review of its use in infants, see A. Arana et al.,Acta
Anaesthesiol. Scand.,2001, 45, 20–29. For a review of paracetamol overdosage, see American
Academy of Pediatrics Committee on Drugs,Pediatrics,2001, 108, 1020–1024 and E. Kozer and
G. Koren,Drug Saf,2001, 24, 503–512.
KROMATOGRAFI

Kromatografi Lapisan Tipis. TA Sistem — Rf 95; TB sistem — Rf 00; sistem TD — Rf 15; sistem TE — Rf
45; sistem TF — Rf 32; sistem TAD — Rf 26; TAE sistem — Rf 77; sistem TAJ — Rf 30; sistem TAK
— Rf 05; sistem TAL — Rf 73. (Larutan besi klorida, biru pudar; larutan kalium permanganat
diasamkan, positif.)

Kromatografi Gas.Sistem GA — parasetamol RI 1665, seni (p-aminofenol) RI 1253, parasetamol-Me RI

1512, seni (p-aminofenol) -Me2 RI 1220; sistem GB — parasetamol RI 1722, seni (p-aminofenol)
RI 1280; sistem GL — paracetamol-Me RI 1630.

Kromatografi Cair Kinerja Tinggi. Sistem HD — k 0,1; sistem HW — k 0,32; sistem HX — RI 264; sistem
HY — RI 241; sistem HZ — waktu retensi 1,9 menit; sistem HAA — waktu retensi 5,6 mnt; sistem
HAM — waktu retensi 2,0 mnt; sistem HAX — waktu retensi 4,8 menit; sistem HAY — waktu
retensi 3,7 mnt