(containing a total of 1300 mg of acetaminophen) release 88% and 95% of the drug within 3 and 5 hours, respectively.¹⁶ Following administration of a single dose of two 650-mg, extended-release caplets, the average maximal plasma concentrations occurred within 0.5 to 3 hours following ingestion and ranged from 6.9 to 14.1 µg/mL. Figure 2 shows the mean pharmacokinetic profile for 24 fasting subjects who received acetaminophen 1300 mg dosed as two extended-release or four regular-strength caplets (two caplets given at 0 and 4 hours).

Distribution

Acetaminophen appears to be widely distributed throughout most body fluids except fat. The apparent volume of distribution of acetaminophen is 0.95 L/kg.¹⁷ A relatively small proportion (10% to 25%) of acetaminophen is bound to plasma proteins and binding is only slightly increased in plasma concentrations associated with overdose.^18,19 The sulfate and glucuronide metabolites do not bind to plasma proteins even at relatively high concentrations.²⁰

Spinal Fluid

Low protein binding and low molecular weight allow acetaminophen to pass through the blood-brain barrier. The peak concentration of acetaminophen in cerebrospinal fluid is reached after 2 to 3 hours.^21,22

Placental Barrier

Analysis of urine samples has demonstrated the passage of unconjugated acetaminophen via placental transfer.²³ When given to the mother in therapeutic doses, acetaminophen crosses the placenta into fetal circulation as early as 30 minutes after ingestion, although the difference in serum concentration between maternal and cord blood is not statistically significant.²⁴ In the fetus, acetaminophen is effectively metabolized by sulfate conjugation.²⁵

Breast Milk

Maternal ingestion of acetaminophen in recommended analgesic doses does not present a risk to the nursing infant. Amounts in milk range from 0.1% to 1.85% of the ingested maternal dose.^26-28 These studies have established that, even at the time of peak acetaminophen concentration in human breast milk, the nursing infant would receive less than 2% of the maternal dose. Accordingly, breast feeding need not be interrupted because of maternal ingestion of recommended doses of acetaminophen.

Metabolism

Acetaminophen is primarily metabolized in the liver by first-order kinetics and involves three principal separate pathways:

a) conjugation with glucuronide

b) conjugation with sulfate

c) oxidation via the cytochrome, P450-dependent, mixed-function oxidative enzyme pathway to form a reactive intermediate metabolite, which conjugates with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates.²⁹ The principal cytochrome P450 isoenzyme involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional pathways.^30-32

Two additional minor pathways also are possibly involved in acetaminophen metabolism:³³

a) hydroxylation to form 3-hydroxy-acetaminophen

b) methoxylation to form 3-methoxy-acetaminophen.

These metabolites are further conjugated with glucuronide or sulfate.

In adults, the majority of acetaminophen is conjugated with glucuronic acid and, to a lesser extent, with sulfate. These glucuronide-, sulfate-, and glutathione-derived metabolites lack biologic activity.⁸ In premature infants, newborns, and young infants, the sulfate conjugate predominates.^23,34

Excretion

The biologic half-life of acetaminophen in normal adults is approximately 2 to 3 hours in the usual dosage range.^21,35 It is somewhat shorter in children and somewhat longer in neonates and in patients with cirrhosis.¹⁸ The elimination half-life is approximately 3 hours for the extended-release product. The elimination half-life of acetaminophen in the cerebrospinal fluid according to pooled data is 3.2 hours.²¹

Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Table 1 0n the following page shows the mean range of acetaminophen urinary metabolite values in healthy subjects using therapeutic doses (10 mg/kg or 1000-mg dose).^36-40 Less than 9% of acetaminophen is excreted unchanged in the urine.³⁷

TABLE 1. Acetaminophen metabolites found in urine

TABLE 2. Adult TYLENOL® acetaminophen preparations

TABLE 3. Pediatric TYLENOL® acetaminophen preparations

Bookmark this page: