Placental transfer of sulindac, sulindac sulfide, and indomethacin in a human placental perfusion model

Lampela, E.; Nuutinen, Laura; Ala‐Kokko, Tero; Parikka, Riitta; Laitinen, Risto S.; Jouppila, Pentti; Vähäkangas, Kirsi

doi:10.1016/s0002-9378(99)70171-7

Cited by 28 publications

(6 citation statements)

References 22 publications

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“…Although this was less than 100%, it was similar to values obtained in our previous report (82.6%) (Shintaku et al, 2007) and other reports (70 -80%) (Schenker et al, 1992;Lampela et al, 1999;Nanovskaya et al, 2002). On the other hand, the mean recovery of diclofenac (92.9%) was also slightly less than 100%.…”

Section: Discussionsupporting

confidence: 92%

Transplacental Pharmacokinetics of Diclofenac in Perfused Human Placenta

et al. 2009

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ABSTRACT:The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of L-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with L-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPT ss value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of L-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min ؊1 , respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with L-lactic acid.The placenta controls the exchange of a variety of materials between mother and fetus (Robertson and Karp, 1976). Maternal-to-fetal transfer of all materials, including drugs, is primarily regulated by the placenta (Knipp et al., 1999). In the placenta, fetal blood neither mixes with nor contacts maternal blood. Fetal blood flows in the placental villi, which projects toward the maternal decidua basalis to form the interstitial (intervillous) space. Syncytiotrophoblast cells form the outermost layer of the placental villi. On the other hand, maternal blood is supplied by the spiral arteries and fills the interstitial space.The use of nonsteroidal anti-inflammatory drugs in pregnant women is known to lead to fetal or neonatal toxicity such as persistent pulmonary hypertension of the newborn (van Marter et al., 1996;Alano et al., 2001) and premature constriction of ductus arteriosus (Menahem, 1991). Diclofenac, a nonsteroidal anti-inflammatory drug, has been classified as one of the most potent inducers of ductus arteriosus constriction in rats (Momma et al., 1984). When given during human full-term pregnancy, diclofenac readily permeates into fetal blood, inhibiting the synthesis of prostaglandins and inducing constriction of the ductus arteriosus, thereby causing pulmonary hypertension in the newborn (Rein et al., 1...

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Section: Discussionsupporting

confidence: 92%

Transplacental Pharmacokinetics of Diclofenac in Perfused Human Placenta

et al. 2009

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“…Antipyrine has been used as a typical passive diffusion marker in human placental perfusion studies. However, we also retrospectively calculated the recovery from the antipyrine concentrations in the influx perfusate and effluents in other studies, and found that it was generally less than 100%, i.e., 80% in the case of Schenker et al (1992), 70% according to Lampela et al (1999), and 75% in the study by Nanovskaya et al (2002). A likely explanation is metabolism of antipyrine in the placenta.…”

Section: Discussionmentioning

confidence: 96%

Kinetic Analysis of the Transport of Salicylic Acid, a Nonsteroidal Anti-inflammatory Drug, across Human Placenta

et al. 2007

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ABSTRACT:The aim of this study was to develop a pharmacokinetic model to describe the transplacental transfer of drugs, based on the human placental perfusion study. The maternal and fetal sides of human placentas were perfused with salicylic acid together with antipyrine, a passive diffusion marker. The drug concentration in the placental tissue was determined at the end of perfusion. A compartment model consisting of maternal space, fetal intravascular space, and placental tissue was fitted to the observed concentration profiles of salicylic acid in the maternal and fetal effluents. The developed model could adequately explain the concentration profiles of salicylic acid in the effluents with influx clearances from maternal and fetal perfusates to placental tissue of 0.0407 and 0.0813 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates (k 2 and k 3 ) of 0.0238 and 0.176 min ؊1 , respectively. The kinetics of antipyrine was adequately described by assuming rapid equilibrium between fetal perfusate and placental tissue compartments. The influx plasma clearance from the maternal side (K؆ 1 ) in humans was estimated by taking into account the protein binding. The K؆ 1 /k 2 value of salicylic acid was 1.07 ml/g cotyledon and was larger than that of antipyrine (0.642 ml/g cotyledon). We evaluated the transplacental transfer kinetics of salicylic acid by human placental perfusion study with various perfusion protocols. Based on the data obtained, we developed a pharmacokinetic model, which should enable us to estimate the influx profile of drugs into umbilical arterial blood from the maternal plasma concentration profile.Exchange of materials between mother and fetus occurs across the placenta (Robertson and Karp, 1976), where fetal blood perfuses the villi and maternal blood fills the interstitial space. The blood-placental barrier consists of trophoblasts, which face the interstitial space, and fetal capillary endothelium (Stulc, 1989). To estimate the distribution of a drug into the fetus, it is essential to investigate the transplacental transfer process.Human placental perfusion, first designed by Schneider et al. (1972), is a useful technique to investigate drug transfer from the maternal to the fetal circulation in humans, because the influx and efflux profiles of the drug can be directly observed. In vivo distribution studies with pregnant animals cannot provide such information and also suffer from the problem of interspecies differences. The placental perfusion technique is also preferable to in vitro methods using cultured human cell lines, such as BeWo or Jar, or membrane vesicles prepared from human placenta (Martel and Keating, 2003;Manley et al., 2005), because physiological metabolism is quite well retained (Nanovskaya et al., 2002). However, many studies using human placental perfusion have provided only simple information, i.e., the ratio of drug concentration in fetal effluent to that in maternal effluent (Heikkinen et al., 2000;Nekhayeva et al., 2005...

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“…To date, 15 studies encompassing 934 fetal MRI cases (including this review) have been reported using scanners at field strengths of 1.5 T or less, and no harmful effects to the developing fetus have been documented. This includes one large study of 400 fetuses, and another involving 20 children with a 3-year follow-up [1, 3, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37]. The second problem, motion artifact, has often been dealt with in the past by the administration of sedatives or paralytics, but the use of these agents obviously increases the complexity and risk of the study.…”

Section: Discussionmentioning

confidence: 99%

“…In a recent study by Levine et al [26], 53 pregnant women underwent MRI examinations of the fetal CNS. They concluded that in 25/53 cases (47%), the additional information provided by MRI was of the type which changes patient counseling.…”

Section: Discussionmentioning

confidence: 99%

Fetal MRI in the Evaluation of Intrauterine Myelomeningocele

et al. 2000

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Background: Accurate fetal imaging is essential to the practice of maternal-fetal medicine. While ultrasonography has been the traditional mainstay of fetal imaging, its ability to resolve critical features of central nervous system (CNS) anatomy remains limited. As interest in intrauterine therapy for myelomeningocele has increased, so has the need for more accurate, noninvasive imaging of the CNS. Fetal magnetic resonance imaging (MRI) promises to fill the gap left by ultrasound. Methods: Thirty-seven MRI scans of fetuses previously diagnosed with myelomeningocele were reviewed by 2 neuroradiologists. The ability of fetal MRI to resolve the commonest CNS stigmata of spina bifida, and the incidence and extent of interobserver error, was assessed. In 4 cases, postnatal MRIs were also available. These were compared to the corresponding fetal studies. Results: The imaging quality with the technique used in this study was excellent, even without the use of maternal or fetal sedation. There were no complications, and the imaging times were minimal. Interobserver error was minimal with respect to the evaluation of ventricular dilatation and hindbrain herniation, but moderate in the description and location of the spinal lesion. As had previously been documented with ultrasonography, a reduction was seen in hindbrain herniation when comparing pre- and postnatal MRIs. Conclusion: It is concluded that fetal MRI is an effective, noninvasive means of assessing fetal CNS anatomy. Its ability to resolve posterior fossa anatomy is superior to ultrasonography while, with respect to the evaluation of hydrocephalus and the level and nature of the spinal lesion, it may be equivalent to inferior. Inclusion of the fetal MRI into the standard diagnostic armamentarium will probably await the next major advance in speed and resolution. It is conceivable that, with further advances, MRI might supplant ultrasonography as the diagnostic tool of choice for evaluation of fetal anomalies including myelomeningocele.

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Placental transfer of sulindac, sulindac sulfide, and indomethacin in a human placental perfusion model

Cited by 28 publications

References 22 publications

Transplacental Pharmacokinetics of Diclofenac in Perfused Human Placenta

Transplacental Pharmacokinetics of Diclofenac in Perfused Human Placenta

Kinetic Analysis of the Transport of Salicylic Acid, a Nonsteroidal Anti-inflammatory Drug, across Human Placenta

Fetal MRI in the Evaluation of Intrauterine Myelomeningocele

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