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Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories.
Arzneimittelforschung. 1998 Sep; 48(9):889-99.A

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 crossover 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-HCl 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% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl 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.) [mean +/- 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 t1/2,ka;1 = 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 t0;1 = 0 h (0-0.37 h) and t0;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 (Cmax) and 3.3 +/- 1.3 h (tmax). There were large differences in the distribution rate between the volunteers. The means of the half-life of the slower distribution (t1/2, alpha) 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 (t1/2, beta) 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 +/- 231 (Vd, beta) and 447 +/- 56 ml/min (Cltot). 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-HCl, probably due to a reduced first-pass metabolisation after rectal administration.

Authors+Show Affiliations

Grünenthal GmbH, Centre of Research, Aachen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Comparative Study
Controlled Clinical Trial
Journal Article

Language

eng

PubMed ID

9793614

Citation

Lintz, W, et al. "Pharmacokinetics of Tramadol and Bioavailability of Enteral Tramadol Formulations. 3rd Communication: Suppositories." Arzneimittel-Forschung, vol. 48, no. 9, 1998, pp. 889-99.
Lintz W, Barth H, Osterloh G, et al. Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories. Arzneimittelforschung. 1998;48(9):889-99.
Lintz, W., Barth, H., Osterloh, G., & Schmidt-Böthelt, E. (1998). Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories. Arzneimittel-Forschung, 48(9), 889-99.
Lintz W, et al. Pharmacokinetics of Tramadol and Bioavailability of Enteral Tramadol Formulations. 3rd Communication: Suppositories. Arzneimittelforschung. 1998;48(9):889-99. PubMed PMID: 9793614.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories. AU - Lintz,W, AU - Barth,H, AU - Osterloh,G, AU - Schmidt-Böthelt,E, PY - 1998/10/30/pubmed PY - 1998/10/30/medline PY - 1998/10/30/entrez SP - 889 EP - 99 JF - Arzneimittel-Forschung JO - Arzneimittelforschung VL - 48 IS - 9 N2 - 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 crossover 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-HCl 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% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl 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.) [mean +/- 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 t1/2,ka;1 = 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 t0;1 = 0 h (0-0.37 h) and t0;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 (Cmax) and 3.3 +/- 1.3 h (tmax). There were large differences in the distribution rate between the volunteers. The means of the half-life of the slower distribution (t1/2, alpha) 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 (t1/2, beta) 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 +/- 231 (Vd, beta) and 447 +/- 56 ml/min (Cltot). 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-HCl, probably due to a reduced first-pass metabolisation after rectal administration. SN - 0004-4172 UR - https://www.unboundmedicine.com/medline/citation/9793614/Pharmacokinetics_of_tramadol_and_bioavailability_of_enteral_tramadol_formulations__3rd_Communication:_suppositories_ DB - PRIME DP - Unbound Medicine ER -