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PHARMACOLOGICAL PROPERTIES
Chemical Names
Tramadol Hydrochloride
(±)cis-2-((dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride.
Paracetamol
N-acetyl-p-aminophenol (4-hydroxyacetanilide)
Pharmacodynamic Properties
Tramadol is a centrally acting analgesic compound. At least two complementary
mechanisms appear applicable, binding of parent and M1 metabolite to m-opioid
receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Paracetamol is another centrally acting analgesic. The exact site and mechanism
of its analgesic action is not clearly defined.
When evaluated in a standard animal model, the combination of tramadol and
paracetamol exhibited a synergistic effect.
Pharmacokinetic Properties
General
Tramadol is administered as a racemate and both the [-] and (+) tons of both
tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma
tramadol and paracetamol following oral administration of one ULTRACET tablet
are shown in Table 1. Tramadol has a slower absorption and longer half-life when
compared to paracetamol.
After a single oral dose of one Tramadol/Paracetamol combination tablet (37.5
mg/325 mg) peak plasma concentrations of 64.3/55.5 ng/ml [(+)-Tramadol/(-)-
Tramadol] and 4.2 mg/ml (Paracetamol) are reached after 1.8 h [(+)-Tramadol/(-)-
Tramadol) and 0.9 h (Paracetamol), respectively. Mean elimination half lives t½ are
5.1/4.7 h [(+)-Tramadob(-)-Tramadol] and 2.5 h (Paracetamol(. Single and multiple
dose pharmacokinetic studies of ULTRACET in volunteers showed no significant
drug interactions between tramadol and paracetamol.
Table 1: Summary of Mean (±SD) Pharmacokinetic Parameters of the (+)- and (-) Enantiomers of Tramadol and M1 and Paracetamol Following A Single Oral Dose Of
One Tramadol/Paracetamol Combination Tablet (37.5 mg/325 mg) in Volunteers
| Parametera |
(+)-Tramadol |
(-)-Tramadol |
(+)-M1 |
(-)-M1 |
Paracetamol |
| Cmax (ng/mL) |
64.3 |
(9.3) |
55.5 |
(8.1) |
10.9 |
(5.7) |
12.8 |
(4.2) |
4.2 |
(0.8) |
| tmax(h) |
1.8 |
(0.6) |
1.8 |
(0.7) |
2.1 |
(0.7) |
2.2 |
(0.7) |
0.9 |
(0.7) |
| CL/F (mL/min) |
588 |
(226) |
736 |
(244) |
-- |
-- |
-- |
-- |
365 |
(84) |
| t½ |
5.1 |
(1.4) |
4.7 |
(1.2) |
7.8 |
(3.0) |
6.2 |
(1.6) |
2.5 |
(0.6) |
a For Paracetamol,
Cmas was measure as µg/mL.
Absorption
Tramadol hydrochloride has a mean absolute bioavailability of approximately 75%
following administration of a single 100 mg oral dose of tramadol 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 in healthy adults.
Oral absorption of paracetamol following administration of
ULTRACET is rapid and
almost complete and occurs primarily in the small intestine. Peak plasma
concentrations of paracetamol occur within 1 hour and are not affected by co-administration with tramadol.
Food Effects
The oral administration of
ULTRACET with food has no significant effect on the
peak plasma concentration or extent of absorption of either tramadol or paracetamol,
so that ULTRACET can be taken independently of meal times.
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%.
Paracetamol 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 paracetamol is bound to plasma protein.
Metabolism
Plasma concentration profiles for tramadol and its M1 metabolite measured following
dosing of ULTRACET in volunteers showed no significant change compared to
dosing with tramadol alone.
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 0- demethylation and glucuronidation or sulfation in the liver. Tramadol is
extensively metabolized by a number of pathways, including CYP2D6.
Paracetamol is primarily metabolized in the liver by first-order kinetics and involves
three principle separate pathways:
• conjugation with glucuronide;
• conjugation with sulfate; and
• oxidation via cytochrome P450 enzyme pathway
Elimination
Tramadol and its metabolites are eliminated primarily by the kidney. The plasma
elimination half-lives of racemic tramadol and M1 are approximately six and seven
hours, respectively. The plasma elimination half-life of racemic tramadol increased
from approximately six hours to seven hours upon multiple dosing of ULTRACET.
The half-life of paracetamol is about 2 to 3 hours in adults. It s somewhat shorter in
children and somewhat longer in neonates and in cirrhotic patients. Paracetamol
is
eliminated from the body primarily by formation of glucuronide and sulfate conjugates in a
dose-depended manner. Less than 9% of paracetamol is excreted unchanged in the urine.
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