Role of P-glycoprotein in transplacental transfer of methadone

Abstract

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).

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

“…However, the transfer of indinavir was unaffected in the presence of ritonavir, most likely because of low P-gp inhibitory potential of ritonavir at clinically relevant concentrations (42). Like indinavir (42) and saquinavir (79) (see above), methadone (80) also showed increased fetal drug transfer after inhibition of P-gp in the perfused human placenta. Nekhayeva et al also reported that MDR1 has been demonstrated to regulate the disposition of methadone across the placental barrier in the perfused human placental model (81).…”

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

“…The intra/extra cellular ratio of methadone was significantly decreased in human ABCB1 transfected cells relative to controls (140). An in vitro model of transplacental transport found that P-gp inhibitor GF120918 increased the transfer of methadone by 30%, and that uptake of methadone in the BeWo cell line was increased in the presence of P-gp inhibitor cyclosporine A (141). The same group demonstrated that methadone transfer was significantly higher in the fetal-tomaternal direction, likely due to the unidirectional activity of P-gp (142).…”

Pharmacogenetics of Chronic Pain and Its Treatment

“…Pgp is known to show extremely broad substrate specificity, including peptides, steroids, therapeutic drug from very large and complex ones as paclitaxel [178] to relatively simple as phenytoin, opioids, and other analgesics [179] or even ions [180–186]. Substrates are often, but not always (e.g., colchicine), amphipathic and relatively hydrophobic.…”