Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb;11(1):e01051.
doi: 10.1002/prp2.1051.

Metabolism of sumatriptan revisited

Timo Pöstges  1 , Matthias Lehr  1
Affiliations

Metabolism of sumatriptan revisited

Timo Pöstges et al. Pharmacol Res Perspect. 2023 Feb.

Abstract

Scientific literature describes that sumatriptan is metabolized by oxidative deamination of its dimethylaminoethyl residue by monoamine oxidase A (MAO A) and not by cytochrome P450 (CYP)-mediated demethylation, as is usual for such structural elements. Using recombinant human enzymes and HPLC-MS analysis, we found that CYP enzymes may also be involved in the metabolism of sumatriptan. The CYP1A2, CYP2C19, and CYP2D6 isoforms converted this drug into N-desmethyl sumatriptan, which was further demethylated to N,N-didesmethyl sumatriptan by CYP1A2 and CYP2D6. Otherwise, sumatriptan and its two desmethyl metabolites were metabolized by recombinant MAO A but not by MAO B to the corresponding acetaldehyde, with sumatriptan being only a poor substrate for MAO A compared to the N-demethylated and the N,N-didemethylated derivatives.

Keywords: cytochrome P450; metabolism; monoamine oxidase; sumatriptan; zolmitriptan.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Metabolism of sumatriptan published in literature
FIGURE 2
FIGURE 2
Formation of a thiazolidine‐4‐carboxylic acid derivative (4) from the MAO A generated aldehyde metabolite (2) of sumatriptan, N‐desmethyl sumatriptan and N,N‐didesmethyl sumatriptan, respectively, and D‐cysteine.
FIGURE 3
FIGURE 3
Superimposed RP‐HPLC/MS chromatograms (single quadrupole, SIM, ESI+, m/z 370.10) of a sample of sumatriptan (black), N‐desmethyl sumatriptan (blue), and N,N‐didesmethyl sumatriptan (green) (10 μM each) after 60 min incubation at 37°C with MAO A and derivatization of the enzyme product (aldehyde 2) with D‐cysteine, and an analogue prepared control sample (red); column: Accucore aQ 2.6 μm, 2.1 × 100 mm, mobile phase: acetonitrile/water/formic acid (10/90/0.1, v/v/v); flow rate: 0.2 ml/min.
FIGURE 4
FIGURE 4
Superimposed RP‐HPLC/MS chromatograms (single quadrupole, SIM, ESI+, m/z 296.15, 282.10, 268.10) of a sample of sumatriptan (10 μM) after 60 min incubation at 37°C with CYP2D6 (black) and an analogue prepared control sample (red); a small signal slightly larger than the noise was observed for N,N‐didesmethyl sumatriptan at a retention time of 9.1 min. Chromatographic conditions: column: Accucore aQ 2.6 μm, 2.1 × 100 mm, mobile phase: acetonitrile/water/formic acid (5/95/0.1, v/v/v); flow rate: 0.2 ml/min.
FIGURE 5
FIGURE 5
Structures of N‐desmethyl sumatriptan, N,N‐didesmethyl sumatriptan, zolmitriptan, and N,N‐dimethyltryptamine.
FIGURE 6
FIGURE 6
Proposed metabolic pathway of sumatriptan
See this image and copyright information in PMC

References

    1. Manallack DT. The pKa distribution of drugs: application to drug discovery. Perspect Med Chem. 2007;1:25‐38. - PMC - PubMed
    1. Karki SB, Dinnocenzo JP. On the mechanism of amine oxidations by P450. Xenobiotica. 1995;25:711‐724. - PubMed
    1. Benedetti MS. Biotransformation of xenobiotics by amine oxidases. Fundam Clin Pharmacol. 2001;15:75‐84. - PubMed
    1. Tipton KF, Benedetti MS. Amine oxidases and the metabolism of xenobiotics. In: Ioannidis C, ed. Enzyme Systems that Metabolize Drugs and Other Xenobiotics. Wiley & Sons Ltd; 2001.
    1. Lang D, Kalgutkar AS. Non‐P450 mediated oxidative metabolism of xenobiotics. In: Lee JS, Obach RS, Fisher MB, eds. Drug Metabolizing Enzymes. Marcel Dekker; 2003:483‐539.

Publication types

MeSH terms

LinkOut - more resources