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Related Experiment Videos

Methadone metabolism by human placenta.

Tatiana N Nanovskaya1, Sujal V Deshmukh, Ilona A Nekhayeva

  • 1Department of Obstetrics and Gynecology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555 0587, USA.

Biochemical Pharmacology
|July 10, 2004
PubMed
Summary

This study identifies CYP19/aromatase as the primary enzyme metabolizing methadone in human placental tissue. Understanding this metabolism is crucial for managing opioid use during pregnancy.

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Area of Science:

  • Pharmacology
  • Biochemistry
  • Reproductive Biology

Background:

  • Methadone pharmacotherapy is standard for pregnant opioid users.
  • Placental metabolism influences fetal exposure to opioids.
  • Identifying placental enzymes is key to understanding drug transfer.

Purpose of the Study:

  • Identify the enzyme responsible for methadone metabolism in human placenta.
  • Determine the kinetics and metabolites of this reaction.
  • Investigate the role of cytochrome P450 enzymes.

Main Methods:

  • Utilized placental tissue from healthy term pregnancies.
  • Assayed methadone metabolism in microsomal fractions.
  • Employed selective cytochrome P450 inhibitors and monoclonal antibodies.

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  • Identified metabolites using HPLC-UV.
  • Determined kinetic parameters (Km, Vmax).
  • Main Results:

    • Trophoblast microsomal fractions showed highest methadone metabolism activity.
    • 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was identified as the primary metabolite.
    • CYP19/aromatase significantly inhibited EDDP formation (88-70% with inhibitors, 80% with antibodies).
    • Apparent kinetic values (Km: 424±92 μM, Vmax: 420±89 pmol/mg/min) were determined for CYP19.
    • Enzyme kinetics in placental microsomes matched cDNA-expressed CYP19.

    Conclusions:

    • CYP19/aromatase is the major enzyme metabolizing methadone to EDDP in human term placentas.
    • This finding is vital for understanding methadone transfer and fetal exposure during pregnancy.
    • Further research can explore therapeutic implications of placental methadone metabolism.