Ultram - Clinical Pharmacology

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The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see PRECAUTIONS, Drug Interactions). Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption

Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.

Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q. i. d. dosing. There is no evidence of self-induction (see Figure 1 and Table 1 below). Figure 1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl given q. i. d.

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 µg/ mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.