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Gary D V Hankins

Publications and source records attributed to Gary D V Hankins.

At least 19 recordsLinked to original sources

Circulating calcitonin gene-related peptide and its placental origins in normotensive and preeclamptic pregnancies.

OBJECTIVE: The present study was designed to determine plasma calcitonin gene-related peptide concentration in both maternal and fetal circulations in normotensive and pre-eclamptic pregnancies and investigate whether placenta is 1 of its origins. STUDY DESIGN: Maternal blood, cord blood, and villous tissue were collected from women in normotensive pregnancies and complicated with pre-eclampsia. Calcitonin gene-related peptide concentrations were determined by radioimmunoassay. Cellular localizations of calcitonin gene-related peptide messenger ribonucleic acid and protein expressions in placental villi were determined by in situ hybridization and immunohistochemistry. RESULTS: The following results were reached: (1) maternal plasma calcitonin gene-related peptide concentrations increased with advancing gestation but fell after delivery; (2) both maternal and cord plasma calcitonin gene-related peptide concentrations were positively correlated with the infant birth weights; (3) compared with normotensive pregnancies, calcitonin gene-related peptide levels in both maternal and cord plasma decreased in pregnancies with pre-eclampsia; (4) in normotensive pregnancies, the plasma calcitonin gene-related peptide of the umbilical vein was higher than the umbilical artery, but no significant differences between vein and artery in pre-eclampsia; (5) calcitonin gene-related peptide messenger ribonucleic acid and protein were expressed by syncytiotrophoblast cells and villous vascular endothelial cells in normotensive pregnancies, but only weak or absent staining was observed in pre-eclamptic placentas; and (6) calcitonin gene-related peptide is secreted by villous tissue in explant culture in a time-dependent manner, but less calcitonin gene-related peptide was produced by villous tissues from patients with pre-eclampsia. CONCLUSION: Calcitonin gene-related peptide may play potential roles in maternal hemodynamic adaptation and fetal growth. Decreased circulating calcitonin gene-related peptide levels may be involved in maternal-fetal pathophysiology of pre-eclampsia. It is novel that placenta villous tissues might be one of the potential sources of calcitonin gene-related peptide during pregnancy.

Adult↗

Role of human placental efflux transporter P-glycoprotein in the transfer of buprenorphine, levo-alpha-acetylmethadol, and paclitaxel.

This study examines the role of placental P-glycoprotein (P-gp) in the transfer of buprenorphine (BUP) and L-alpha-acetylmethadol (LAAM) across the dually perfused human placental lobule. BUP (10 ng/mL) and LAAM (35 ng/mL) were perfused in the maternal-to-fetal direction. The following kinetic parameters were determined: fetal transfer rate (TR (f)), maternal clearance (Cl (m)), and clearance index (Cl (index)). The opiates were perfused in the presence of P-gp inhibitor GF120918 (experimental group) and in its absence (control group). The kinetic parameters for the control group were set at 100% and were as follows for LAAM in the experimental group: TR (f), 123 +/- 20%, Cl (m) 116 +/- 23%, and Cl (index) 123 +/- 22% ( P < 0.05). The corresponding parameters for BUP were not different from controls. The data indicate that LAAM, but not BUP, is extruded by the efflux transporter P-gp. Therefore, it is reasonable to assume that the activity of P-gp could be one of the factors affecting the extent of fetal exposure to LAAM during pregnancy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Identification of glyburide metabolites formed by hepatic and placental microsomes of humans and baboons.

Glyburide (glibenclamide) is a second-generation sulfonylurea used for treatment of type-2 and gestational diabetes mellitus. To date, two glyburide metabolites have been identified in maternal urine: namely, 4-trans-hydroxycyclohexyl glyburide and 3-cis-hydroxycyclohexyl glyburide. The use of glyburide to treat gestational diabetes prompted us to investigate its metabolism by the placenta. The metabolism of glyburide by microsomal preparations from human and baboon placenta was compared with metabolism by their livers. The metabolites formed by the microsomes of the four tissues were identified by high-performance liquid chromatography-mass spectrometry using retention times, ion current (extracted at m/z 510), and selected-ion monitoring. The data obtained revealed the formation of six distinct hydroxylated derivatives of glyburide by each of the four microsomal preparations. However, the amounts of the six metabolites formed by the placentas were a fraction of that formed by the livers. Moreover, the relative quantities of each metabolite formed differed between species as well as between the two tissues. Also, the structure of the unidentified metabolites was determined by comparison with synthesized standards. These metabolites were identified as the 4-cis-hydroxycyclohexyl glyburide, 3-trans-hydroxycyclohexyl glyburide, and 2-trans-hydroxycyclohexyl glyburide. Therefore, one glyburide metabolite remains to be identified, but the data we obtained allowed us to suggest its structure.

Adult↗

The effect of opiates on the activity of human placental aromatase/CYP19.

Aromatase, cytochrome P450 19, is a key enzyme in the biosynthesis of estrogens by the human placenta. It is also the major placental enzyme that metabolizes the opiates L-acetylmethadol (LAAM), methadone, and buprenorphine (BUP). Methadone and BUP are used in treatment of the opiate addict and are competitive inhibitors of testosterone conversion to estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)) by aromatase. The aim of this investigation is to determine the effect of 20 opiates, which can be administered to pregnant patients for therapeutic indications or abused, on E(2) and E(3) formation by placental aromatase. Data obtained indicated that the opiates increased, inhibited, or had no effect on aromatase activity. Their effect on E(3) formation was more pronounced than that on E(2) due to the lower affinity of 16-OHT than testosterone to aromatase. The K(i) values for the opiates that inhibited E(3) formation were sufentanil, 7 +/- 1 microM; LAAM, 13 +/- 8 microM; fentanyl, 25 +/- 5 microM; oxycodone, 92 +/- 22 microM; codeine, 218 +/- 69 microM; (+)-pentazocine, 225 +/- 73 microM. The agonists morphine, heroin, hydromorphone, oxymorphone, hydrocodone, propoxyphene, meperidine, levorphanol, dextrorphan, and (-)-pentazocine and the antagonists naloxone and naltrexone caused an increase in E(3) formation by 124-160% of control but had no effect on E(2) formation. Moreover, oxycodone and codeine did not inhibit E(2) formation and the IC(50) values for fentanyl, sufentanil, and (+)-pentazocine were >1000 microM. It is unlikely that the acute administration of the opiates that inhibit estrogen formation would affect maternal and/or neonatal outcome. However, the effects of abusing any of them during the entire pregnancy are unclear at this time.

Aromatase↗

Management of uterine hyperstimulation with concomitant use of oxytocin and terbutaline.

The purpose of this study was to evaluate the efficacy of the concomitant use of subcutaneous terbutaline and oxytocin for the management of uterine hyperstimulation. Patients in active labor receiving intravenous oxytocin who developed uterine hyperstimulation were randomly assigned to receive either oxytocin discontinuation or administration of subcutaneous terbutaline while maintaining the oxytocin infusion. Time to resolution of hyperstimulation was the primary end point. Twenty-nine patients were enrolled. The most frequent types of hyperstimulation were tachysystole (26%) and mixed patterns (26%). Resolution time was significantly shorter in the combination therapy versus control ( P = 0.002). Persistence of hyperstimulation 15 minutes after intervention was seen in 53% of the women in the control group versus 0% of the women in the study group. No significant differences were noted in the Apgar scores, rates of cesarean sections, or chorioamnionitis. In the management of uterine hyperstimulation, subcutaneous terbutaline without discontinuation of oxytocin is more effective than the traditional approach of oxytocin discontinuation.

Adult↗

Effect of human serum albumin on transplacental transfer of glyburide.

Glyburide is a second-generation sulfonylurea hypoglycemic drug used for the treatment of select women with pregestational and gestational diabetes mellitus (GDM). In vitro and in vivo investigations demonstrated its very low transplacental transfer to the fetal circulation. However, the factors influencing its low transfer across the human placenta remain unclear. Therefore, the goal of the current investigation was to determine the effect of human serum albumin (HSA) on the transfer and distribution of glyburide across the human placenta. To achieve this goal, the technique of dual perfusion of the placental lobule was utilized. The effect of HSA on the transfer of glyburide was determined at the range of glyburide to HSA molar ratios of 1:2-1:100. The transfer rate of free/unbound glyburide to the fetal circuit was 73+/-10% of the freely diffusible marker compound antipyrine (AP). Data obtained indicates the dependence of glyburide transfer and its retention by the placental tissue on the concentration of HSA.

Female↗

Transfer of metformin across the dually perfused human placental lobule.

OBJECTIVE: The purpose of this study was to determine the transfer characteristics of metformin across placentas that were obtained from uncomplicated pregnancies and from patients with gestational diabetes mellitus. STUDY DESIGN: The technique of dual perfusion of placental lobule was used. Metformin, 5 microg/mL and its [14C]-isotope were co-transfused with the marker compound antipyrine, 20 microg/mL and its [3H]-isotope from the maternal to fetal circuit. The drug content in both circulations and placental tissue was determined by liquid scintillation spectrometry. RESULTS: The transfer of metformin across term human placentas that were obtained from uncomplicated pregnancies was rapid and was not different from that in placentas that were obtained from patients with gestational diabetes mellitus. Metformin is distributed between the maternal and fetal circuits, with reliable amounts retained by the tissue. CONCLUSION: In an ex vivo model system, metformin was transferred readily from the maternal to fetal circuit across placentas that were obtained from uncomplicated pregnancies and pregnancies with gestational diabetes mellitus.

Diabetes, Gestational↗

Methadone metabolism by early gestational age placentas.

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 Km) did not change with gestation, but the activity of the enzyme (Vmax) 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.

Aromatase↗

Labor-associated gene expression in the human uterine fundus, lower segment, and cervix.

BACKGROUND: Preterm labor, failure to progress, and postpartum hemorrhage are the common causes of maternal and neonatal mortality or morbidity. All result from defects in the complex mechanisms controlling labor, which coordinate changes in the uterine fundus, lower segment, and cervix. We aimed to assess labor-associated gene expression profiles in these functionally distinct areas of the human uterus by using microarrays. METHODS AND FINDINGS: Samples of uterine fundus, lower segment, and cervix were obtained from patients at term (mean +/- SD = 39.1 +/- 0.5 wk) prior to the onset of labor (n = 6), or in active phase of labor with spontaneous onset (n = 7). Expression of 12,626 genes was evaluated using microarrays (Human Genome U95A; Affymetrix) and compared between labor and non-labor samples. Genes with the largest labor-associated change and the lowest variability in expression are likely to be fundamental for parturition, so gene expression was ranked accordingly. From 500 genes with the highest rank we identified genes with similar expression profiles using two independent clustering techniques. Sets of genes with a probability of chance grouping by both techniques less than 0.01 represented 71.2%, 81.8%, and 79.8% of the 500 genes in the fundus, lower segment, and cervix, respectively. We identified 14, 14, and 12 those sets of genes in the fundus, lower segment, and cervix, respectively. This enabled networks of co-regulated and co-expressed genes to be discovered. Many genes within the same cluster shared similar functions or had functions pertinent to the process of labor. CONCLUSIONS: Our results provide support for many of the established processes of parturition and also describe novel-to-labor genes not previously associated with this process. The elucidation of these mechanisms likely to be fundamental for controlling labor is an important prerequisite to the development of effective treatments for major obstetric problems--including prematurity, with its long-term consequences to the health of mother and offspring.

Cervix Uteri↗

The effect of methadone and buprenorphine on human placental aromatase.

Methadone and buprenorphine (BUP) are used for treatment of the pregnant opiate addict. CYP19/aromatase is the major placental enzyme responsible for the metabolism of methadone to 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and BUP to norbuprenorphine (norBUP). The aim of this investigation was to determine the effects of methadone and BUP on the activity of placental microsomal aromatase in the conversion of its endogenous substrates testosterone to 17beta-estradiol (E(2)) and 16alpha-hydroxytestosterone (16-OHT) to estriol (E(3)). The conversion of testosterone and 16-OHT by human placental microsomes exhibited saturation kinetics, and the apparent K(m) values were 0.2 +/- 1 and 6 +/- 3 microM, respectively. V(max) values for E(2) and E(3) formation were 70 +/- 16 and 28 +/- 10 pmol/mg proteinmin, respectively. Also, data obtained revealed that methadone and BUP are competitive inhibitors of testosterone conversion to E(2) and 16-OHT to E(3). The K(i) for methadone inhibition of E(2) and E(3) formation were 393 +/-144 and 53 +/- 28 microM, respectively, and for BUP the K(i) was 36 +/- 9 and 6 +/- 1 microM. The higher potency of the two opiates and their metabolites in inhibiting E(3) formation is in agreement with the lower affinity of 16-OHT than testosterone to aromatase. Moreover, the metabolites EDDP and norBUP were weaker inhibitors of aromatase than their parent compounds. The determined inhibition constants of methadone and BUP for E(3) formation by a cDNA-expressed CYP19 preparation were similar to those for placental microsomes. Therefore, data reported here suggest that methadone, BUP, and their metabolites are inhibitors of androgen aromatization in the placental biosynthesis of estrogens.

Aromatase↗

The role of stillbirth prevention and late preterm (near-term) births.

Stillbirth remains an important cause of fetal loss in both the term and late-preterm (near-term) pregnancy. As ongoing research further elucidates the causes of intrauterine fetal demise (IUFD), strategies can be tested to reduce its occurrence. Currently, reduction of IUFD in the term and late preterm infants should focus on reduction or elimination of risk factors (eg, smoking and control of medical conditions) and enhanced fetal surveillance in those pregnancies identified to be at increased risk.

Female↗

Cesarean section on request at 39 weeks: impact on shoulder dystocia, fetal trauma, neonatal encephalopathy, and intrauterine fetal demise.

PURPOSE: The purpose of this analysis was to determine the impact on specific forms of neonatal morbidity and mortality by allowing women to opt for delivery by elective cesarean section at 39 weeks of gestation (EGA). According to the National Vital Statistics Reports, over 70% of deliveries in the U.S. annually are at gestational ages>or=39 weeks EGA. Estimating that over 4 million deliveries occur annually in the United States, this would yield approximately 3 million pregnancies wherein the woman may exercise her choice for either primary or repeat cesarean section at 39 weeks EGA or at the point when labor is established. METHODS: A search was conducted using Ovid Medline spanning the past 10 years using the following key words: fetal trauma, shoulder dystocia, brachial plexus palsy, neonatal skull fracture, obstetrical trauma, traumatic delivery, intrauterine fetal demise, stillbirth, fetal demise, and neonatal encephalopathy. Using this search technique, over 2100 articles were identified. The abstracts were reviewed and pertinent articles were chosen for further consideration. The identified articles and their applicable references were obtained for inclusion in this review. Preference was given to publications on or after the year 2000 with the exception of classical or sentinel articles, which were included without regard to year of publication. RESULTS: Four major categories of neonatal morbidity and mortality are discussed: Shoulder dystocia: Accepting that we do not have a successful method for the prediction or prevention of shoulder dystocia, the question becomes, "What is the chance that a baby will sustain a permanent brachial plexus injury at delivery?" Additionally, is there a significant protective effect of cesarean section in reducing the risk of such injury? Currently, the occurrence rate of brachial plexus palsy at the time of vaginal delivery ranges from 0.047% to 0.6% and for cesarean section from 0.0042% to 0.095%. Using a composite estimate of the risk of 0.15% for vaginal deliveries and applying it to the 3 million deliveries>or=39 weeks EGA, approximately 4500 cases of brachial plexus palsy would occur. If only 15% of these injuries were permanent, 675 permanent brachial plexus palsies would occur annually. If the risk of permanent injury is 1 in 10,000 as reported by Chauhan, 300 permanent brachial plexus palsies would occur annually in the United States. The range then for permanent brachial plexus injury that could be avoided with cesarean section on request would appear to vary between 1 in 5000 and 1 in 10,000 vaginal births. Fetal trauma: The incidence of significant birth trauma varies from 0.2 to 1 to 2 per 1000 births. The use of sequential instruments, for example, vacuum followed by forceps or vice versa, is specifically associated with an unacceptably high injury rate. Intrapartum-related neonatal deaths of vertex singleton fetuses with birthweights>2500 g from traumatic cranial or cervical spine injury secondary to vacuum- or forceps-assisted vaginal delivery are still occurring. Overall, the frequency of significant fetal injury is significantly greater with vaginal delivery, especially operative vaginal delivery, than with cesarean section for the nonlaboring woman at 39 weeks EGA or near term when early labor has been established. Neonatal encephalopathy: The prevalence of moderate to severe neonatal encephalopathy is 3.8/1000 term live births with a neonatal fatality rate of 9.1%. In 4% to 10% of cases, the etiology appears to be pure intrapartum hypoxia. Intrapartum hypoxia superimposed on antepartum risk factors may account for up to 25% of the moderate to severe encephalopathies, according to one cohort. A paradox in the data thus far is that infants born to nonlaboring women delivered by cesarean section had an 83% reduction in the occurrence of moderate or severe encephalopathy. Considering a prevalence of moderate or severe neonatal encephalopathy of 0.38% and applying it to the 3 million deliveries occurring at >or=39 weeks EGA in the United States annually, 11,400 cases of moderate to severe encephalopathy would occur. The rate of encephalopathy observed in infants delivered by cesarean section would yield approximately 1938 cases. This net difference in moderate to severe encephalopathy would represent 9462 cases annually in the United States that could be prevented with elective cesarean section. Although cesarean delivery may be protective for the development of neonatal encephalopathy, to date it has not proven to be protective of long-term neurologic injury in the form of cerebral palsy with or without mental retardation and/or seizure disorders. Intrauterine fetal demise: Copper reported that the rate of stillbirth is consistent from 23 to 40 weeks EGA with about 5% of all stillbirths occurring at each week of gestation. Yudkin reported a rate of 0.6 stillbirths per 1000 live births from 33 to 39 weeks EGA. After 39 weeks EGA, a significant increase in the stillbirth rate was reported (1.9 per 1000 live births). Fretts reported on fetal deaths per 1000 live births from 37 to 41 weeks of gestational age, showing that the rate progressively increased from 1.3 to 4.6 with each week of gestation. It can be estimated that delivery at 39 weeks EGA would prevent 2 fetal deaths per 1000 living fetuses. This would translate into the prevention of as many as 6000 intrauterine fetal demises in the United States annually-an impact that far exceeds any other strategy implemented for stillbirth reduction thus far. CONCLUSION: It is reasonable to inform the pregnant woman of the risk of each of the above categories, in addition to counseling her regarding the potential risks of a cesarean section for the current and any subsequent pregnancies. The clinician's role should be to provide the best evidence-based counseling possible to the pregnant woman and to respect her autonomy and decision-making capabilities when considering route of delivery.

Birth Injuries↗

Pharmacokinetics and pharmacotherapy of thionamides in pregnancy.

Hyperthyroidism occurs in approximately 1 in every 1000 to 2000 pregnancies. Although the signs and symptoms of the disease are similar in the pregnant and nonpregnant patient, the complications of hyperthyroidism can have even more profound consequences for the mother and fetus during gestation. These include maternal heart failure, preeclampsia, miscarriage, and preterm labor; as well as fetal loss and low birth weight. Furthermore, thyroid function and laboratory testing for hyperthyroidism are altered in pregnancy. The gestational increase in thyroid size, increased thyroid-binding globulin levels, increased serum total T4 and total T3 levels, and decreased thyroid stimulating hormone levels often confuses the evaluation of the thyroid status in pregnancy. Worldwide, the thionamides-propylthiouracil, methimazole, and carbimazole-have been used in pregnancy for the treatment of hyperthyroidism. However, propylthiouracil has been the drug of choice in the United States because it is believed to have less potential to induce fetal/neonatal hypothyrodism, to cross the placenta and into breast milk to a lesser degree, and to be less teratogenic than methimazole or carbimazole. None of the above have been substantiated in more recent studies. The pharmacokinetics of the thionamides in the pregnant and nonpregnant states, as well as the pharmacotherapeutic recommendation for hyperthyroidism will be reviewed.

Antithyroid Agents↗

Obstetric litigation is asphyxiating our maternity services.

Obstetric care in the United States, as judged by maternal mortality, neonatal mortality, stillbirth rates, or any other metric, has never been better. Despite this, litigation over "bad outcomes" is threatening the specialty, not only now, but into the future. Despite damage to our specialty, the injured party often benefits little, if at all, from the process. Potential solutions include an emphasis on evidence-based medicine, a qualification and review process for medical experts, and a more rational and fair health court system.

Cerebral Palsy↗

Effects of nicotine-specific antibodies, Nic311 and Nic-IgG, on the transfer of nicotine across the human placenta.

The adverse effects of smoking during pregnancy on fetal development are, in part, due to nicotine. These effects may be due to the actions of nicotine in fetal circulation or on placental functions. In pregnant rats, vaccination with a nicotine immunogen reduces the transfer of nicotine from the maternal to fetal circulation. However, extrapolation of these results to pregnant women might not be valid due to the well-recognized differences between human and rat placentas. In the current investigation, the effects of nicotine-specific antibodies on the transfer of nicotine from the maternal to fetal circuit of the dually perfused human placental lobule were determined. Two types of nicotine-specific antibodies were investigated; nicotine-specific mouse monoclonal antibody (Nic311, K(d) for nicotine 60nM) and IgG from rabbits vaccinated with a nicotine immunogen (Nic-IgG, K(d) 1.6nM). Transfer of the antibodies from maternal to fetal circuits was negligible. Both rabbit Nic-IgG and, to a lesser extent, mouse monoclonal Nic311 significantly reduced nicotine transfer from the maternal to fetal circuit as well as the retention of the drug by placental tissue. These effects were mediated by a substantial increase in the protein binding of nicotine and a reduction in the unbound nicotine concentration. Therefore, the data cited in this report suggest that the use of nicotine-specific antibodies might reduce fetal exposure to the drug, and that antibody affinity for nicotine is a key determinant of the extent of nicotine transfer.

Animals↗

Role of P-glycoprotein in transplacental transfer of methadone.

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).

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Bidirectional transfer of methadone across human placenta.

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.

Dose-Response Relationship, Drug↗