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Food Effects When ULTRACET was administered with food, the time to peak plasma concentration was delayed for ap-proximately 35 minutes for tramadol and almost one hour for acetaminophen. However, peak plasma concentra-tion or the extent of absorption of either tramadol or acetaminophen were not affected. The clinical signifi-cance of this difference is unknown. Distribution Text Continues Below
The volume of distribution of tramadol was 2.6 and 2.9 L/ kg in male and female subjects, respectively, follow-ing a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentra-tion up to 10 µg/ mL. Saturation of plasma protein bind-ing 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. 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-demethy-lation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmaco-logically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhi-bition, which may affect the therapeutic response (see PRECAUTIONS, Drug Interactions). Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are "poor metabolizers" of debriso-quine, dextromethorphan, tricyclic antidepressants, among other drugs. Based on a population PK analy-sis of Phase 1 studies in healthy subjects, concentra-tions of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were 40% lower. Page: << Prev | 1 | 2 | 3 | 4 | 5 | Next >>
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