Tramadol pharmacokinetics and molecular data

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pharmacokinetics

Absorption

Food Effects

Distribution

Metabolism

Elimination

Gender

Geriatric

Hepatic

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Absorption

The absolute bioavailability of tramadol from ULTRACET tablets has not been determined. Tramadol hydrochloride has a mean absolute bioavailability of approximately 75% following administration of a single 100 mg oral dose of ULTRAM tablets. The mean peak plasma concentration of racemic tramadol and M1 after administration of two ULTRACET tablets occurs at approximately two and three hours, respectively, post-dose.

Food Effects

When ULTRACET was administered with food, the time to peak plasma concentration was delayed for approximately 35 minutes for tramadol and almost one hour for acetaminophen. However, peak plasma concentration or the extent of absorption of either tramadol or acetaminophen were not affected. The clinical significance of this difference is unknown.

Distribution

The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Acetaminophen appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 L/kg. A relative small portion (~20%) of acetaminophen is bound to plasma protein.

Metabolism

Following oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response

Elimination

Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The plasma elimination half-lives of racemic tramadol and M1 are approximately 5-6 and 7 hours, respectively, after administration of ULTRACET. The apparent plasma elimination half-life of racemic tramadol increased to 7-9 hours upon multiple dosing of ULTRACET. The half-life of acetaminophen is about 2 to 3 hours in adults. It is somewhat shorter in children and somewhat longer in neonates and in cirrhotic patients. Acetaminophen is eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a dose-dependent manner. Less than 9% of acetaminophen is excreted unchanged in the urine.

Gender

Tramadol clearance was 20% higher in female subjects compared to males on four phase I studies of ULTRACET in 50 male and 34 female healthy subjects. The clinical significance of this difference is unknown.

Geriatric

A population pharmacokinetic analysis of data obtained from a clinical trial in patients with chronic pain treated with ULTRACET which included 55 patients between 65 and 75 years of age and 19 patients over 75 years of age, showed no significant changes in pharmacokinetics of tramadol and acetaminophen in elderly patients with normal renal and hepatic function.

Hepatic

The pharmacokinetics and tolerability of ULTRACET in patients with impaired hepatic function has not been studied. Since tramadol and acetaminophen are both extensively metabolized by the liver, the use of ULTRACET in patients with hepatic impairment is not recommended

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Adapted from the FDA Package Insert.