Ultracet Mechanism of Action

Pharmacology: Tramadol is a centrally acting analgesic compound. At least 2 complementary mechanisms appear applicable, binding of parent and M1 metabolite to mu-opioid receptors and weak inhibition of re-uptake 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.
Pharmacokinetics: General: Tramadol is administered as a racemate and both the (-) and (+) forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of plasma tramadol and paracetamol following oral administration of 1 Ultracet tablet are shown in the table. Tramadol has a slower absorption and longer half-life when compared to paracetamol. (See table.)
After a single oral dose of 1 tramadol/paracetamol combination tablet (37.5 mg/325 mg), peak plasma concentrations of 64.3/55.5 ng/mL [(+)-tramadol/(-)-tramadol] and 4.2 mcg/mL (paracetamol) are reached after 1.8 hrs [(+)-tramadol/(-)-tramadol] and 0.9 hrs (paracetamol), respectively. Mean elimination half-lives (t_1/2) are 5.1/4.7 hrs [(+)-tramadol/(-)-tramadol] and 2.5 hrs (paracetamol).
Single- and multiple-dose pharmacokinetic studies of Ultracet in volunteers showed no significant drug interactions between tramadol and paracetamol.

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Absorption: Tramadol HCl 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 2 Ultracet tablets occurs at approximately 2 and 3 hrs, respectively, postdose 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 hr 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 IV 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 O-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 3 principle separate pathways: Conjugation with glucuronide; conjugation with sulfate; and oxidation via cytochrome P-450 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 6 and 7 hrs, respectively. The plasma elimination half-life of racemic tramadol increased from approximately 6-7 hrs upon multiple dosing of Ultracet.
The half-life of paracetamol is about 2-3 hrs in adults. It is 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-dependent manner. Less than 9% of paracetamol is excreted unchanged in the urine.
Toxicology: Preclinical Safety Data: Tramadol/Paracetamol Combination: There are no animal or laboratory studies on the combination product (tramadol and paracetamol) to evaluate carcinogenesis, mutagenesis or impairment of fertility.
No drug-related teratogenic effects were observed in the progeny of rats treated orally with the combination of tramadol and paracetamol. The tramadol/paracetamol combination product was shown to be embryotoxic and fetotoxic in rats at a maternally toxic dose (50/434 mg/kg tramadol/paracetamol) 8.3 times the maximum human dose but was not teratogenic at this dose level. Embryo and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs. Lower and less severe maternally toxic dosages (10/87 and 25/217 mg/kg tramadol/paracetamol) did not produce embryo or fetal toxicity.
Carcinogenicity/Mutagenicity: Tramadol HCl: A slight but statistically significant increase in 2 common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice (dosing orally up to 30 mg/kg for approximately 2 years, although the study was not done with the maximum tolerated dose). This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study.
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters.
Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
Impairment of Fertility/Effect on Reproduction: No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats.
Tramadol was evaluated in peri- and postnatal studies in rats. Progeny of dams receiving oral (gavage) dose levels of ≥50 mg/kg had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (6-10 times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20, 25 or 40 mg/kg. Maternal toxicity was observed at all dose levels of tramadol in this study, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.