Bidirectional transfer of methadone across human placenta

Abstract

Methadone maintenance programs are considered the standard of care for the pregnant opiate addict. However, data on changes in methadone pharmacokinetics (PK) during pregnancy are limited and do not include its disposition by the placenta due to obvious ethical and safety considerations. Accordingly, investigations in our laboratory are focusing on human placental disposition of opiates including methadone. Recently, we reported on methadone metabolism by placental aromatase and provide here data on its bidirectional transfer across the tissue utilizing the technique of dual perfusion of placental lobule. The concentrations of the opiate transfused into the term placental tissue were those reported for its in vivo levels in the maternal serum of women under treatment with the drug. Data obtained indicated that the opiate has no adverse effects on placental viability and functional parameters and that it is retained by the tissue. Also, methadone transfer and its clearance index in the fetal to maternal direction (0.97 ± 0.05) was significantly higher (P < 0.05) than in the maternal to fetal (0.83 ± 0.09). The observed asymmetry in methadone transfer could be explained by the unidirectional activity of the efflux transporter P glycoprotein (P-gp) that is highly expressed in variable amounts in trophoblast tissue. Therefore, placental disposition of methadone might be an important contributor to the regulation of its concentration in the fetal circulation and consequently may affect the incidence and intensity of neonatal abstinence syndrome for women treated with the drug during pregnancy.

Introduction

Maternal and neonatal morbidity and mortality are significantly increased by opiate abuse during pregnancy [1], [2]. The goal of methadone treatment programs is detoxification of the adult patient, but for the pregnant woman, the well-being of the fetus is an additional concern. Fetal distress and other complications can accompany fluctuations in maternal serum levels of the opiate [3], [4]. Methadone, a long-acting opiate that minimizes changes in maternal serum levels, has been the drug of choice for treatment of the pregnant opiate addict, and is the only pharmacotherapy approved by the US Food and Drug Administration for this patient population. A combination of methadone maintenance therapy and adequate prenatal care reduces the incidence of adverse medical, obstetric, fetal, and neonatal outcomes [5], [6]. Pregnant women not continuing in methadone treatment programs could relapse, with consequences for fetal development, and perinatal and neonatal outcome [7]. A major concern for prenatal exposure to opiates, therapeutically or abused, is the incidence of neonatal abstinence syndrome (NAS). Approximately 60–80% of the newborns exposed to methadone in utero experience NAS [8], [9], [10], but it is unclear whether its intensity is dependent on the dose of the opiate. A number of investigators were unable to demonstrate a dose–response relationship [8], [9], [11], [12], while others reported a correlation between maternal methadone dose, its serum level, and intensity of NAS [13], [14]. On the other hand, a preliminary report on a recent investigation indicated a lack of correlation between methadone dose and NAS [15]. In a review of the literature, this controversy was attributed, at least in part, to the lack of a defined causal relationship and to reports that are poorly controlled for confounding factors, thus leading the authors to correlate higher doses of methadone with severity of NAS [16].

The dose of methadone used for treatment of the pregnant opiate addict, according to a review of the literature by Warner et al. [17], ranges between 10 and 90 mg/day, with a mean of 50 mg/day. A recent investigation indicated that higher doses of the drug (between 50 and 150 mg/day) might be needed to achieve the maternal serum trough levels necessary to prevent withdrawal symptoms in both mother and fetus, with an occasional need for even higher doses towards the end of pregnancy or during the third trimester [18]. These data underscore the need to better understand the pharmacokinetics (PK) of methadone in the pregnant patient, a well-recognized issue for most therapeutic agents. An important contributor to the changes in the pharmacokinetics of a drug during pregnancy is the role of human placenta in its disposition, since one of the goals of the tissue is to protect the fetus from the effects of xenobiotics. Placental disposition of a drug, e.g., methadone, includes its transfer, distribution, and metabolism by trophoblast enzymes, but data on these processes and functions during pregnancy are scarce. There are at least two major reasons for the lack of data. The first is the obvious ethical and safety concern accompanying such in vivo investigations and the second is the unique structure of human placenta that has restricted extrapolation of the information obtained from laboratory animals [19]. Nevertheless, there is data on the concentrations of methadone at delivery in the amniotic fluid, maternal and cord blood, indicating that the opiate is readily transferred across the placenta [8], [20], [21]. This data, though valuable, addresses the concentration of methadone at a single time point only. Therefore, there is a lack of data on the kinetics for methadone transfer across the human placenta and its disposition by the tissue. This data is essential for better understanding of the factors affecting the amounts of the opiate that reach the fetal circulation and, consequently, its effect on neonatal outcome.

Data on the kinetics for transfer of a drug across human placenta can be obtained using the technique of dual perfusion of a placental lobule. This technique has proven a good predictor of in vivo conditions [22], [23]. Recently, the technique was utilized in our laboratory to investigate the transplacental transfer of the opiates buprenorphine (BUP) and l-α-acetylmethadol (LAAM, a congener of methadone). The data obtained revealed that the extent of transplacental transfer of LAAM to the fetal circuit is higher than that for BUP [24], [25]. Moreover, the major placental enzyme responsible for the metabolism of BUP, LAAM [26], [27], and methadone [28] was cytochrome P 450 (CYP) 19 (known also as aromatase) and not CYP 3A4, as reported for human liver and intestine [29], [30], [31], [32]. These data point to the role of the placenta in disposition of these opiates during pregnancy.

Therefore, the goal of this investigation is to determine the kinetics for the bidirectional transfer of methadone across term human placenta, its distribution between the tissue, maternal, and fetal circuits, and its effects on the viability and functional parameters of the tissue.