Methadone metabolism by human placenta

Tatiana Nanovskaya, Sujal V. Deshmukh, Ilona A. Nekhayeva, Olga L. Zharikova, Gary Hankins, Mahmoud Ahmed

Research output: Contribution to journalArticle

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Abstract

Methadone pharmacotherapy is considered the standard for treatment of the pregnant heroin/opioid addict. One of the factors affecting the transfer kinetics of opioids across human placenta and their levels in the fetal circulation is their metabolism by the tissue. The aim of this investigation is to identify the enzyme(s) responsible for the metabolism of methadone, determine the kinetics of the reaction and the metabolites formed utilizing placental tissue obtained from term healthy pregnancies. Microsomal fractions of trophoblast tissue homogenates had the highest activity in catalyzing the metabolism of methadone. The product formed was identified by HPLC-UV as 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Inhibitors selective for cytochrome P450 (CYP) isozymes were used to identify the enzyme catalyzing the biotransformation of methadone. Aminoglutethimide and 4- hydroxyandrostenedione inhibited EDDP formation by 88 and 70%, respectively, suggesting that CYP19/aromatase is the enzyme catalyzing the reaction. This was confirmed by the effect of monoclonal antibodies raised against CYP19 that caused an 80% inhibition of the reaction. The apparent Km and V max values for the CYP19 catalyzed metabolism of methadone to EDDP were 424 ± 92 μM and 420 ± 89 pmol (mg protein)-1 min-1, respectively. Kinetic analysis of a cDNA-expressed CYP19 for the metabolism of methadone to EDDP was identical to that by placental microsomes. Taken together, these data indicate that CYP19/aromatase is the major enzyme responsible for the metabolism of methadone to EDDP in term human placentas obtained from healthy pregnancies.

Original languageEnglish (US)
Pages (from-to)583-591
Number of pages9
JournalBiochemical Pharmacology
Volume68
Issue number3
DOIs
StatePublished - Aug 1 2004

Fingerprint

Aromatase
Methadone
Metabolism
Placenta
Enzymes
Tissue
Opioid Analgesics
Aminoglutethimide
Drug therapy
Transfer Factor
Pregnancy
Enzyme kinetics
Kinetics
Heroin
Trophoblasts
Biotransformation
Metabolites
Microsomes
Cytochrome P-450 Enzyme System
Isoenzymes

Keywords

  • 2-ethyl-5-methyl-3,3-diphenylpyrroline
  • 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine
  • Aromatase
  • BUP
  • buprenorphine
  • CYP
  • cytochrome P450
  • EDDP
  • EMDP
  • Human placenta
  • L-α-acetylmethadol
  • LAAM
  • Metabolism
  • Methadone
  • Pregnancy
  • TCA
  • trichloroacetic acid

ASJC Scopus subject areas

  • Pharmacology

Cite this

Nanovskaya, T., Deshmukh, S. V., Nekhayeva, I. A., Zharikova, O. L., Hankins, G., & Ahmed, M. (2004). Methadone metabolism by human placenta. Biochemical Pharmacology, 68(3), 583-591. https://doi.org/10.1016/j.bcp.2004.04.011

Methadone metabolism by human placenta. / Nanovskaya, Tatiana; Deshmukh, Sujal V.; Nekhayeva, Ilona A.; Zharikova, Olga L.; Hankins, Gary; Ahmed, Mahmoud.

In: Biochemical Pharmacology, Vol. 68, No. 3, 01.08.2004, p. 583-591.

Research output: Contribution to journalArticle

Nanovskaya, T, Deshmukh, SV, Nekhayeva, IA, Zharikova, OL, Hankins, G & Ahmed, M 2004, 'Methadone metabolism by human placenta', Biochemical Pharmacology, vol. 68, no. 3, pp. 583-591. https://doi.org/10.1016/j.bcp.2004.04.011
Nanovskaya T, Deshmukh SV, Nekhayeva IA, Zharikova OL, Hankins G, Ahmed M. Methadone metabolism by human placenta. Biochemical Pharmacology. 2004 Aug 1;68(3):583-591. https://doi.org/10.1016/j.bcp.2004.04.011
Nanovskaya, Tatiana ; Deshmukh, Sujal V. ; Nekhayeva, Ilona A. ; Zharikova, Olga L. ; Hankins, Gary ; Ahmed, Mahmoud. / Methadone metabolism by human placenta. In: Biochemical Pharmacology. 2004 ; Vol. 68, No. 3. pp. 583-591.
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