One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon Cytochrome P-450(2D6) and as such is subject to both metabolic induction and inhibition which may affect the therapeutic response (see DRUG INTERACTIONS). Tramado1 and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramado1 and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.

Absorption:

Rac

emic tramado1os rapidl

and almost c

pletely absorbed a

er oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramado1 and M1 occurs at two and three hours, resp

tively, after administration in healthy adults. In general, both enantiomers of tramado1 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 tramado1 and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction (see TABLE 1).

TABLE 1 Mean (%CV) Pharmacokinetic Parameters for Racemic Tramado1 and M1 Metabolite

Population/Dosage Regimena Parent Drug/Metabolite Peak Conc (ng/ml) Time to Peak (hrs) Clearance/Fb (ml/min/kg) t½ (hrs)
Healthy Adults, Tramado1 592 (30) 2.3 (61) 5.90 (25) 6.7 (15)
100 mg qid, MD p.o. M1 110 (29) 2.4 (46) c 7.0 (14)
Healthy Adults, Tramado1 308 (25) 1.6 (63) 8.50 (31) 5.6 (20)
100 mg SD p.o. M1 55.0 (36) 3.0 (51) c 6.7 (16)
Geriatric, Tramado1 208 (31) 2.1 (19) 6.89 (25) 7.0 (23)
(>75 yrs) 50 mg SD p.o. M1 d d c d
Hepatic Impaired, Tramado1 217 (11) 1.9 (16) 4.23 (56) 13.3 (11)
50 mg SD p.o. M1 19.4 (12) 9.8 (20) c 18.5 (15)
Renal Impaired, Tramado1 c c 4.23 (54) 10.6 (31)
CLcr 10-30 ml/min 100 mg SD i.v. M1 c c c 11.5 (40)
Renal Impaired, Tramado1 c c 3.73 (17) 11.0 (29)
CLcr<5 ml/min 100 mg SD i.v. M1 c c c 16.9 (18)
a SD = Single dose, MD = Multiple dose, p.o. = Oral administration, i.v. = Intravenous administration, qid = Four times daily
b F represents the oral bioavailability of tramado1
c Not applicable
d Not measured

Food Effect on Absorption: Oral administration of tramado1 HCl with food does not significantly affect its rate or extent of absorption, therefore, tramado1 HCl can be administered without regard to food.

Distribution: The volume of distribution of tramado1 was 2.6 and 2.9 L/kg in male and female subjects, respectively following a 100 mg intravenous dose. The binding of tramado1 to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 mcg/ml. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Although not confirmed in humans, tramado1 has been shown in rats to cross the blood-brain barrier.

Metabolism: Tramado1 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 metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyltramado1, denoted M1) is pharmacologically active in animal models. Production of M1 is dependent on the CYP2D6 isoenzyme of cytochrome P-450 and as such is subject to both metabolic induction and inhibition which may affect the therapeutic response (see DRUG INTERACTIONS).

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. After a single oral dose of tramado1, concentrations of tramado1 were only slightly higher in "poor metabolizers" versus "extensive met

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