Tramadol pharmacokinetics and molecular data

# Pharmacokinetics
Absorption
Food Effects
Distribution
Metabolism
Elimination
Gender
Geriatric
Hepatic

## Absorption
The absolute bioavailability of tramadol from Tramadol 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 Tramadol tablets occurs at approximately two and three
hours, respectively, post-dose. Return to top

## Food Effects
When Tramadol 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. Return to top

## 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 g/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. Return to top

## 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. Return to top

## 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 Tramadol . The apparent plasma
elimination half-life of racemic tramadol increased to 7-9 hours upon multiple dosing of Tramadol .
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%
-f acetaminophen is excreted unchanged in the urine. Return to top

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

## 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. Return to top

## 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 Tramadol in patients with hepatic impairment is not recommended. Return to top
Adapted from the FDA Package Insert.