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Am J Perinatol 2006; 23(5): 287-294
DOI: 10.1055/s-2006-947160
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Methadone Metabolism by Early Gestational Age Placentas

Todd Lewis Hieronymus1 , Tatiana N. Nanovskaya2 , Sujal V. Deshmukh3 , Ricardo Vargas1 , Gary D.V Hankins1 , Mahmoud S. Ahmed1 , 2
  • 1Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas
  • 2Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas
  • 3Merck & Co., Inc., Boston, Massachusetts
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Publication History

Publication Date:
23 June 2006 (online)

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ABSTRACT

The objective of this study was to identify the enzyme that metabolizes methadone in preterm placentas. Microsomal fractions were obtained from preterm (17 to 34 weeks) placentas (36 total; 12 per each gestational age group) and their activity in metabolizing methadone to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was determined. The enzyme catalyzing the reaction was identified by using chemical inhibitors selective for various cytochrome P450 isozymes and monoclonal antibodies raised against them. The metabolism of methadone by microsomes revealed saturation kinetics. Methadone was N-demethylated to EDDP by aromatase. The affinity of methadone to aromatase (apparent K m) did not change with gestation, but the activity of the enzyme (V max) increased and varied widely between individual placentas. Aromatase/CYP19 is the placental enzyme metabolizing methadone during pregnancy. The variability in enzyme activity among individuals should be reflected by the concentration of methadone in the fetal circulation and might be one of the factors affecting the incidence and intensity of neonatal abstinence syndrome.

KEYWORDS

Pregnancy - methadone maintenance programs - human placental aromatase/CYP19

REFERENCES

  • 1 Allen M H. Detoxification considerations in the medical management of substance abuse in pregnancy.  Bull NY Acad Med. 1991;  67 270-276
    PubMedGoogle Scholar
  • 2 Warner E A, Kosten T R, O'Connor P G. Pharmacotherapy for opioid and cocaine abuse.  Med Clin North Am. 1997;  81 909-925
    CrossrefPubMedGoogle Scholar
  • 3 Drozdick III J, Berghella V, Hill M, Kaltenbach K. Methadone trough levels in pregnancy.  Am J Obstet Gynecol. 2002;  187 1184-1188
    CrossrefPubMedGoogle Scholar
  • 4 Doberczak T M, Kandall S R, Friedmann P. Relationship between maternal methadone dosage, maternal-neonatal methadone levels, and neonatal withdrawal.  Obstet Gynecol. 1993;  81 936-940
    PubMedGoogle Scholar
  • 5 Dashe J S, Sheffield J S, Olscher D A, Todd S J, Jackson G L, Wendell Jr G D. Relationship between maternal methadone dosage and neonatal withdrawal.  Obstet Gynecol. 2002;  100 1244-1249
    CrossrefPubMedGoogle Scholar
  • 6 Rosen T S, Pippenger C E. Disposition of methadone and its relationship to severity of withdrawal in the newborn.  Addict Dis. 1975;  2 169-178
    PubMedGoogle Scholar
  • 7 Kandall S R, Albin S, Gartner L M, Lee K, Eidelman A, Lowinson J. The narcotic-dependent mother: fetal and neonatal consequences.  Early Hum Dev. 1977;  1 159-169
    CrossrefPubMedGoogle Scholar
  • 8 Mack G, Thomas D, Giles W, Buchanan N. Methadone levels and neonatal withdrawal.  J Paediatr Child Health. 1991;  27 96-100
    PubMedGoogle Scholar
  • 9 Berghella V, Lim P J, Hill M K, Cherpes J, Chennat J, Kaltenbach K. Maternal methadone dose and neonatal withdrawal.  Am J Obstet Gynecol. 2003;  189 312-317
    CrossrefPubMedGoogle Scholar
  • 10 Doberczak T M, Kandall S R, Wilets I. Neonatal opiate abstinence syndrome in term and preterm infants.  J Pediatr. 1991;  118 933-937
    CrossrefPubMedGoogle Scholar
  • 11 Frederiksen M C. Physiologic changes in pregnancy and their effect on drug disposition.  Semin Perinatol. 2001;  25 120-123
    CrossrefPubMedGoogle Scholar
  • 12 Loebstein R, Koren G. Clinical relevance of therapeutic drug monitoring during pregnancy.  Ther Drug Monit. 2002;  24 15-22
    CrossrefPubMedGoogle Scholar
  • 13 Juchau M R. Drug biotransformation in the placenta.  Pharmacol Ther. 1980;  8 501-524
    CrossrefPubMedGoogle Scholar
  • 14 Pasanen M, Pelkonen O. The expression and environmental regulation of P450 enzymes in human placenta.  Crit Rev Toxicol. 1994;  24 211-229
    CrossrefPubMedGoogle Scholar
  • 15 Pasanen M, Hukkanen J, Pelkonen O et al.. Expression of xenobiotic-metabolizing cytochrome P450 forms in human full-term placenta.  Biochem Pharmacol. 1996;  51 403-411
    CrossrefPubMedGoogle Scholar
  • 16 Nanovskaya T N, Deshmukh S V, Nekhayeva I A, Zharikova O L, Hankins G DV, Ahmed M S. Methadone metabolism by human placenta.  Biochem Pharmacol. 2004;  68 583-591
    CrossrefPubMedGoogle Scholar
  • 17 Moody D E, Alburges M E, Parker R J, Collins J M, Strong J M. The involvement of cytochrome P450 3A4 in the demethylation of L-α-acetylmethadol (LAAM), norLAAM, and methadone.  Drug Metab Dispos. 1997;  25 1347-1353
    PubMedGoogle Scholar
  • 18 Foster D J, Somogyi A A, Bochner F. Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4.  Br J Clin Pharmacol. 1999;  47 403-412
    CrossrefPubMedGoogle Scholar
  • 19 Iribarne C, Berthou F, Baird S et al.. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes.  Chem Res Toxicol. 1996;  9 365-373
    CrossrefPubMedGoogle Scholar
  • 20 Ferrari A, Coccia C PR, Bertolini A, Sternieri E. Methadone-metabolism, pharmacokinetics, and interactions.  Pharmacol Res. 2004;  50 551-559
    CrossrefPubMedGoogle Scholar
  • 21 Gerber J G, Rhodes R J, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19.  Chirality. 2004;  16 36-44
    CrossrefPubMedGoogle Scholar
  • 22 Oda Y, Kharasch E D. Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation.  J Pharmacol Exp Ther. 2001;  298 1021-1032
    PubMedGoogle Scholar
  • 23 Beckett A H, Taylor J F, Casy A F, Hassan M MA. The biotransformation of methadone in man: synthesis and identification of a major metabolite.  J Pharm Pharmacol. 1968;  20 754-762
    PubMedGoogle Scholar
  • 24 Pohland A, Boaz H E, Sullivan H R. Synthesis and identification of metabolites resulting from the biotransformation of dl-methadone in man and in the rat.  J Med Chem. 1971;  14 194-197
    CrossrefPubMedGoogle Scholar
  • 25 Billings R E, Booher R, Smits S, Pohland A, McMahon R E. Metabolism of acetylmethadol: a sensitive assay for noracetylmethadol and the identification of a new active metabolite.  J Med Chem. 1973;  16 305-306
    CrossrefPubMedGoogle Scholar
  • 26 Hakkola J, Raunio H, Purkunen R et al.. Detection of cytochrome P450 gene expression in human placenta in first trimester of pregnancy.  Biochem Pharmacol. 1996;  52 379-383
    CrossrefPubMedGoogle Scholar
  • 27 Hakkola J, Pasanen M, Hukkanen J et al.. Expression of xenobiotic-metabolizing cytochrome P450 forms in human full-term placenta.  Biochem Pharmacol. 1996;  51 403-411
    CrossrefPubMedGoogle Scholar
  • 28 Kitawaki J, Yoshida N, Osawa Y. An enzyme-linked immunosorbent assay for quantitation of aromatase cytochrome P-450.  Endocrinology. 1989;  124 1417-1423
    CrossrefPubMedGoogle Scholar
  • 29 Stresser D M, Turner S D, McNamara J et al.. A high-throughput screen to identify inhibitors of aromatase (CYP19).  Anal Biochem. 2000;  284 427-430
    CrossrefPubMedGoogle Scholar
  • 30 Kitawaki J, Inoue S, Tamura T et al.. Increasing aromatase cytochrome P-450 level in human placenta during pregnancy: studied by immunohistochemistry and enzyme-linked immunosorbent assay.  Endocrinology. 1992;  130 2751-2757
    CrossrefPubMedGoogle Scholar
  • 31 Deshmukh S V, Nanovskaya T N, Ahmed M S. Aromatase is the major enzyme metabolizing buprenorphine in human placenta.  J Pharmacol Exp Ther. 2003;  306 1099-1105
    CrossrefPubMedGoogle Scholar
  • 32 Ayub M, Levell M J. Structure-activity relationships of the inhibition of human placental aromatase by imidazole drugs including ketoconazole.  J Steroid Biochem. 1988;  31 65-72
    CrossrefPubMedGoogle Scholar

Mahmoud S AhmedPh.D. 

Departments of Obstetrics & Gynecology and Pharmacology & Toxicology, University of Texas Medical Branch

301 University Blvd., Galveston, TX

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