Aromatase Is the Major Enzyme Metabolizing Buprenorphine in Human Placenta

Deshmukh, Sujal V.; Nanovskaya, Tatiana; Ahmed, Mahmoud S.

doi:10.1124/jpet.103.053199

Cited by 47 publications

(30 citation statements)

References 30 publications

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“…Accordingly, placental disposition of methadone would be achieved by its metabolism of the drug or its efflux back to the maternal circulation. Earlier reports from our laboratory provided evidence supporting our working hypothesis by identifying aromatase/CYP 19 as the major enzyme responsible for the metabolism of the opiates BUP to norBUP [27], LAAM to norLAAM [28], and methadone to EDDP [5]. It is interesting to note that the major enzyme responsible for the metabolism of these opiates in human liver and intestine is CYP 3A4 [29][30][31].…”

Section: Discussionsupporting

confidence: 72%

Role of P-glycoprotein in transplacental transfer of methadone

Nanovskaya

Nekhayeva

Karunaratne

et al. 2005

Biochemical Pharmacology

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Methadone is the therapeutic agent of choice for treatment of the pregnant opiate addict. However, little is known on the factors affecting its concentration in the fetal circulation during pregnancy and how it might relate to neonatal outcome. Therefore, a better understanding of the function of placental metabolic enzymes and transporters should add to the knowledge of the role of the tissue in the disposition of methadone and its relation to neonatal outcome. We hypothesized that the expression and activity of the placental efflux transporter P-glycoprotein (P-gp) would affect the transfer of methadone to the fetal circulation. Data obtained utilizing dual perfusion of placental lobule and monolayers of Be-Wo cell line indicated that methadone is extruded by P-gp. Transfer of methadone to the fetal circuit was increased by 30% in the presence of the P-gp inhibitor GF120918 while the transfer of paclitaxel, a typical substrate of the glycoprotein, was increased by 50%. In the Be-Wo cell line, methadone and paclitaxel uptake was also increased in the presence of the P-gp inhibitor cyclosporin A. Moreover, the expression of P-gp in placental brush-border membranes varied between term placentas. Taken together, these data strongly suggest that the concentration of methadone in the fetal circulation is affected by the expression and activity of P-gp. It is reasonable to speculate that placental disposition of methadone affects its concentration in the fetal circulation. If true, this may also be directly related to the incidence and intensity of neonatal abstinence syndrome (NAS).

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Section: Discussionsupporting

confidence: 72%

Role of P-glycoprotein in transplacental transfer of methadone

Nanovskaya

Nekhayeva

Karunaratne

et al. 2005

Biochemical Pharmacology

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“…Some data suggest that the placental transfer of this opioid may be limited in comparison with others, such as methadone, thereby limiting fetal exposure and the development of dependency. 126 Deshmukh and colleagues 127 have demonstrated that a large proportion of buprenorphine is metabolized to Norbuprenorphine, the only metabolite formed as determined by high-performance liquid chromatography and mass spectrometry, by placental aromatase (CYP 19) within the microsomal fraction of the trophoblast.…”

Section: Opiate Addictionsmentioning

confidence: 99%

Management of Addiction Disorders in Pregnancy

Helmbrecht

Thiagarajah

2008

Journal of Addiction Medicine

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In this article, we will review the prevalence of addiction disorders in pregnancy and the impact that it has on perinatal morbidity and mortality. We will then review effective screening techniques and propose a management scheme for achieving short-term abstinence leading to the ultimate goal of long-term recovery. The various medical and obstetric complications unique to this patient population will be discussed as well as the specific adverse effects of substance abuse on placentation and the developing fetus. Finally, medications proven efficacious in the treatment of addiction disorders will be reviewed in the context of their use in the pregnant population.

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“…Aromatase has been implicated in the metabolism and, specifically, the demethylation of a number of drugs in vitro, including methadone, 18 buprenorphine, 31 and cocaine, 32 but the role that this enzyme plays in the metabolism of xenobiotic medications in humans has not been directly examined before in a clinical study. The clinical trial reported here examined the Data are presented as mean T SD (n = 15).…”

Section: Discussionmentioning

confidence: 99%

Reduced Methadone Clearance During Aromatase Inhibition

Thong²,

Flockhart³

2012

Journal of Clinical Psychopharmacology

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Methadone is increasingly used in pain management and is a cornerstone in the treatment of opiate withdrawal. It is subject to highly variable clearance among patients. The complete metabolic disposition of methadone is likely to involve a number of enzymes, including specifically CYP2B6. Previous studies in vitro suggest that metabolism by aromatase may also contribute. Single-dose methadone pharmacokinetics (2 mg, intravenous) were studied in 15 healthy postmenopausal women in the presence and absence of a potent aromatase inhibitor, letrozole. A sequential design was used, involving a control period followed by treatment with letrozole (2.5 mg/d, 11 days), in which each subject served as her own control. On average, letrozole treatment reduced methadone systemic clearance by 22% (P = 0.001), increased methadone AUC by 23% (P = 0.007), and increased elimination half-life by 21% (P = 0.042). The plasma parent-to-metabolite ratio also increased (P = 0.009), and there was a linear relationship (R2 = 0.74) between change in this plasma ratio and change in methadone AUC0-∞. In contrast, there was no such association with change in apparent urinary methadone clearance. Letrozole did not change methadone distribution half-life or its volume of distribution. Overall, these data demonstrate a significant decrease in methadone clearance during coadministration of letrozole, consistent with decreased metabolism brought about by aromatase inhibition. An involvement of aromatase in the disposition of methadone may help explain the difficulty in methadone dosing and suggests a broader role for this catalyst of endogenous steroid metabolism in xenobiotic drug disposition.

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Aromatase Is the Major Enzyme Metabolizing Buprenorphine in Human Placenta

Cited by 47 publications

References 30 publications

Role of P-glycoprotein in transplacental transfer of methadone

Role of P-glycoprotein in transplacental transfer of methadone

Management of Addiction Disorders in Pregnancy

Reduced Methadone Clearance During Aromatase Inhibition

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