Ultram Clinical Pharmacology

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Ultram - Clinical Pharmacology [Tramadol]

Table 1 Mean (% CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite

a SD = Single dose, MD = Multiple dose, p. o. = Oral administration, i. v. = Intravenous administration, q. i. d. = Four times daily b F represents the oral bioavailability of tramadol c Not applicable d Not measured

Food Effects

Oral administration of ULTRAM with food does not significantly affect its rate or extent of absorption, therefore, ULTRAM can be administered without regard to food.

Distribution

The volume of distribution of tramadol was 2.6 and 2.9 liters/ 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 inde-pendent of concentration up to 10 痢/ mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Metabolism

Tramadol is extensively metabolized after oral administration. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabo-lites. The major metabolic pathways appear to be N-and O-demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramadol, denoted M1) 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 (see PRECAUTIONS, Drug Interaction).

Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. These individuals are "poor metabolizers" of debrisoquine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower. Concomitant therapy with inhibitors of CYP2D6 such as fluoxe-tine, paroxetine and quinidine could result in significant drug interactions.