Skip to main content
Log in

The metabolism of tramadol by human liver microsomes

  • Clinical Pharmacology
  • Published:
The clinical investigator Aims and scope Submit manuscript


The metabolism of tramadol was investigated in vitro using microsomal fractions of human liver. The parent compound and its main metabolites were determined by a newly developed high performance liquid chromatography assay. O-demethylation of tramadol was found to be stereoselective. The Vmax of the O-demethylation of (−)-tramadol was 210 pmol·mg·min−1, whereas (+)-tramadol was O-demethylated with a Vmax of 125 pmol·mg−1·min−1. The Km for both enantiomers was determined to be 210 μM. O-demethylation was inhibited competitively by quinidine (ki=15 nM) and propafenone (ki=34 nM). N-demethylation was also stereoselective, preferentially metabolizing the (+)-enantiomer. Whereas O-demethylation displayed monophasic Michaelis-Menten kinetics, N-demethylation was best described by a two-site model. Competitive inhibition of the O-demethylation both by quinidine and propafenone suggests that O-demethylation is carried out by P-450IID6.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others



high performance liquid chromatography

ki :

inhibitory constant

km :

apparent Michaelis-Menten constant


O-demethylated metabolite of tramadol


N-demethylated metabolite of tramadol


nicotinamide-adenine dinucleotide phosphate



vmax :

maximum velocity of the reaction


  1. Dayer P, Gasser R, Gut J, Kronbach T, Robertz GM, Eichelbaum M, Meyer UA (1984) Characterization of common genetic defect of cytochrome P-450 function (debrisoquinesparteine type polymorphism)-increased Michaelis constant (km) and loss of stereoselectivity of bufuralol 1-hydroxylation in poor metabolizers. Biochem Biophys Res Commun 125:374–380

    Google Scholar 

  2. Eichelbaum M, Gross AS (1990) The genetic polymorphism of debrisoquine/sparteine metabolism — clinical aspects. Pharmacol Ther 46:377–394

    Google Scholar 

  3. Eichelbaum M, Spannbrucker N, Dengler HJ (1978) A probably genetic defect of the metabolism of sparteine. In: Gorrod JW (ed) Biological oxidation of nitrogen. Elsevier North-Holland, Amsterdam, pp 113–118

    Google Scholar 

  4. Kroemer HK, Mikus G, Kronbach T, Meyer UA, Eichelbaum M (1989) In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone. Clin Pharmacol Ther 45:28–33

    Google Scholar 

  5. Lintz W, Erlacin S, Frankus E, Uragg H (1981) Metabolismus von Tramadol bei Mensch und Tier. Arzneimittelforschung/Drug Res 31:1932–1943

    Google Scholar 

  6. Meyer UA (1990) Genetic polymorphisms of drug metabolism. Fundam Clin Pharmacol 4:595–615

    Google Scholar 

  7. Osikowska-Evers BA, Eichelbaum M (1986) A sensitive capillary GC assay for the determination of sparteine oxidation products in microsomal fractions of human liver. Life Sci 38:1775–1782

    Google Scholar 

  8. Otton SV, Crewe HK, Lennard MS, Tucker GT, Woods HF (1988) Use of quinidine inhibition to define the role of the sparteine/debrisoquine cytochrome P450 in metoprolol oxidation by human liver microsomes. J Pharmacol Exp Ther 247:242–247

    Google Scholar 

Download references

Author information

Authors and Affiliations


Rights and permissions

Reprints and permissions

About this article

Cite this article

Paar, W.D., Frankus, P. & Dengler, H.J. The metabolism of tramadol by human liver microsomes. Clin Investig 70, 708–710 (1992).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI:

Key words