Titre du document / Document title

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations : 3rd communication : Suppositories

Auteur(s) / Author(s)

LINTZ W. ⁽¹⁾ ; BARTH H. ⁽¹⁾ ; OSTERLOH G. ⁽¹⁾ ; SCHMIDT-BÖTHELT E. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Grünenthal GmbH, Centre of Research, Aachen, ALLEMAGNE

Résumé / Abstract

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after rectal administration of tramadol suppositories (Tramal®) were determined in a balanced cross-over study in 10 female volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one rectally (1 suppository) and one intravenously (2 ml of a solution for injection). The formulations were administered in the morning, the washout period was one week. Serum concentrations of tramadol-HC were determined by gas chromatography-mass spectrometry and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability was calculated model-independently. The extent of the absolute bioavailability (F) of tramadol in the suppositories, based on AUC data, was 77.0% (point estimate; n = 10) with a 95% confidence interval of 70.8-83.6% (ANOVA_log). The areas under the serum concentration curves of tramadol-HC calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2933 + 304 h ng/ml (rectal) and 3775 ± 446 h ng/ml (i.v.) [x ± SD; n = 10]. Optimal curve fitting of the serum concentration data after rectal administration presupposed the existence of two absorption sites with different absorption rates and lag times. Under this premise the absorption half-lives were t_1/2,ka;l = 1.7 h (median; range: 1.1-3.1 h) and t₁/2_,ka;2 = 0.98 h (0.35-1.9 h), and the corresponding lag times were t_0;1 = 0 h (0-0.37 h) and t_0:2 = 0.66 h (0.31-3.5 h). The relative portion of the more rapidly absorbed quantity of tramadol varied between 9.2 and 50 % (median: 28 %). The maxima of the serum concentration curves were reached 2-6 h after rectal administration; the means of the individual maxima were 294 ± 50 ng/ml (c_max) and 3.3 + 1.3 h (t_max). There were large differences in the distribution rate between the volunteers. The means of the half-life of the slower distribution (t_1/2,α) were 1.38 + 0.47 h (rectal; n = 10) and 1.78 ± 0.63 h (i.v.; n = 7). In the terminal phase the biological half-life (t_1/2,β) was 5.7 + 1.0 h (rectal) and 5.7 ± 0.9 h (i.v.), respectively. The values determined after i.v. injection for the total distribution volume and the total clearance were 216 ± 23 1 (V_d.β) and 447 + 56 ml/min (Cl_tot). The results show that after rectal administration of the tramadol suppositories the absorption of the active ingredient is rapid enough for therapeutic purposes and that the extent of the absolute bioavailability is higher than after oral administration of tramadol-HCI, probably due to a reduced first-pass metabolisation after rectal administration.

Revue / Journal Title

Arzneimittel-Forschung   ISSN 0004-4172   CODEN ARZNAD 

Source / Source

1998, vol. 48, n^o9, pp. 889-899 (31 ref.)

Langue / Language

Anglais

Editeur / Publisher

Cantor, Aulendorf, ALLEMAGNE  (1951) (Revue)

Mots-clés anglais / English Keywords

Tramadol ; Analgesic ; Bioavailability ; Pharmacokinetics ; Rectal administration ; Intravenous administration ; Single dose ; Female ; Serum ; Blood ;

Mots-clés français / French Keywords

Tramadol ; Analgésique ; Biodisponibilité ; Pharmacocinétique ; Voie rectale ; Voie intraveineuse ; Dose unique ; Femelle ; Sérum ; Sang ;

Mots-clés espagnols / Spanish Keywords

Tramadol ; Analgésico ; Biodisponibilidad ; Farmacocinética ; Vía rectal ; Vía intravenosa ; Dosis única ; Hembra ; Suero ; Sangre ;

Localisation / Location

INIST-CNRS, Cote INIST : 565, 35400007097513.0020