Perfusion studies of glyburide transfer across the human placenta: Implications for fetal safety

Kraemer, Jennifer M.; Klein, Julia; Lubetsky, Angelika; Koren, Gideon

doi:10.1016/j.ajog.2005.12.005

Cited by 98 publications

(51 citation statements)

References 10 publications

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“…Particularly open placental perfusions are commonly used to assess the drug clearance at steady-state concentration the concentration gradient, accumulation of the test substance in either one of the both circuits may be observed 24 . Of note, the addition of the test substance only to the fetal circuit is also feasible and can reveal the mechanism of transport across the placental barrier of this particular substance 25 .…”

Section: Discussionmentioning

confidence: 99%

Determination of the Transport Rate of Xenobiotics and Nanomaterials Across the Placenta using the <em>ex vivo</em> Human Placental Perfusion Model

Grafmüller

Manser

Krug

et al. 2013

JoVE

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Decades ago the human placenta was thought to be an impenetrable barrier between mother and unborn child. However, the discovery of thalidomide-induced birth defects and many later studies afterwards proved the opposite. Today several harmful xenobiotics like nicotine, heroin, methadone or drugs as well as environmental pollutants were described to overcome this barrier. With the growing use of nanotechnology, the placenta is likely to come into contact with novel nanoparticles either accidentally through exposure or intentionally in the case of potential nanomedical applications. Data from animal experiments cannot be extrapolated to humans because the placenta is the most species-specific mammalian organ 1 . Therefore, the ex vivo dual recirculating human placental perfusion, developed by Panigel et al. in 1967 2 and continuously modified by Schneider et al. in 1972 3 , can serve as an excellent model to study the transfer of xenobiotics or particles.Here, we focus on the ex vivo dual recirculating human placental perfusion protocol and its further development to acquire reproducible results.The placentae were obtained after informed consent of the mothers from uncomplicated term pregnancies undergoing caesarean delivery. The fetal and maternal vessels of an intact cotyledon were cannulated and perfused at least for five hours. As a model particle fluorescently labelled polystyrene particles with sizes of 80 and 500 nm in diameter were added to the maternal circuit. The 80 nm particles were able to cross the placental barrier and provide a perfect example for a substance which is transferred across the placenta to the fetus while the 500 nm particles were retained in the placental tissue or maternal circuit. The ex vivo human placental perfusion model is one of few models providing reliable information about the transport behavior of xenobiotics at an important tissue barrier which delivers predictive and clinical relevant data. Video LinkThe video component of this article can be found at

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Section: Discussionmentioning

confidence: 99%

Determination of the Transport Rate of Xenobiotics and Nanomaterials Across the Placenta using the <em>ex vivo</em> Human Placental Perfusion Model

Grafmüller

Manser

Krug

et al. 2013

JoVE

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“…62 Furthermore, placental perfusion studies can provide valuable information regarding both transfer and biotransformation of different drugs in the human placenta. [65][66][67] To date, these studies have been used with drugs not usually prescribed for cancer treatment. However, they can serve as a model for the assessment of placental transfer and effect of cancer chemotherapy and thus add important information regarding fetal safety.…”

Section: Future Perspectivesmentioning

confidence: 99%

The treatment of Hodgkin's and non-Hodgkin's lymphoma in pregnancy

Pereg

Koren²,

Lishner³

2007

Haematologica

117

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Lymphoma is the fourth most frequent malignancy diagnosed during pregnancy, occurring in approximately 1:6000 of deliveries. Its occurrence may increase due to the current trend to postpone pregnancy until later in life and the suggested high incidence of AIDS-related non-Hodgkin's lymphoma in developing countries. The relatively rare occurrence of pregnancy-associated lymphoma precludes the conduction of large, prospective studies to examine diagnostic, management and outcome issues. Chemotherapy and radiotherapy during the first trimester are associated with increased risk of congenital malformations and this risk diminishes as pregnancy advances. In the vast majority of cases, when lymphoma is diagnosed during the first trimester, treatment with a standard chemotherapy regimen, following pregnancy termination should be recommended. In the rare patients at low risk, such as those with stage 1 Hodgkin's lymphoma or indolent non-Hodgkin's lymphoma, therapy can be delayed until the end of the first trimester and of embryogenesis while keeping the patients under close observation. When lymphoma is diagnosed during the second and third trimesters, evidence exists suggesting that full-dose chemotherapy can be administered safely without apparent increased risk of severe adverse fetal outcome.

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“…Exemplo de droga que é retirada da circulação fetal e retornada à materna é a glibenclamida, sulfoniluréia de segunda geração, usada como hipoglicemiante oral, que age estimulando células pancreáticas a liberarem insulina endógena 8,16 . Além de apresentar alta ligação a proteínas plasmáticas, com pequena fração livre da droga para atravessar a barreira placentária, e de ter meia-vida curta, baixo volume de distribuição e rápida depuração, a glibenclamida é transportada por BCRP e MRP3, do compartimento fetal para o materno 13 .…”

Section: Proteínas Transportadorasunclassified

“…Estudo randomizado controlado, com 404 pacientes com diabetes gestacional, em uso de glibenclamida, mostrou níveis indetectáveis da droga no sangue fetal (cordão umbilical) 8 . Em modelo experimental de perfusão placentária, com concentrações equivalentes iniciais de glibenclamida (200 ng/mL) no lado materno e fetal, mostrou-se diminuição de 63% na concentração fetal, com fl uxo constante do compartimento fetal para o materno, mesmo contra o gradiente de concentração da droga 16 . Outro estudo experimental demonstrou níveis fetais insignifi cantes de glibenclamida, mesmo com concentração materna oito vezes maior que a concentração terapêutica 17 .…”

Section: Proteínas Transportadorasunclassified

Transferência placentária de drogas

Cavalli¹,

Baraldi²,

Cunha³

2006

Rev. Bras. Ginecol. Obstet.

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ResumoGrávidas podem depender do uso de medicações para minimizar os agravos da doença preexistente. A gravidez, por si só, pode causar situações que comprometem o bem-estar materno, como náuseas e vômitos, as quais necessitam de tratamento. O obstetra deve estar atento à transferência placentária de drogas e à exposição do feto a agentes teratogênicos ou tóxicos, que podem comprometer o seu desenvolvimento ou mesmo sua vida futura.O transporte através da placenta envolve o movimento de moléculas entre três compartimentos: sangue materno, citoplasma do sinciciotrofoblasto e sangue fetal. Esse movimento pode ocorrer pelos seguintes mecanismos: difusão simples, difusão facilitada, transporte ativo, bombas classe P, V, F e grande família ABC e endocitose. Com o uso de anticonvulsivantes a incidência de malformações maiores em recém-nascidos expostos é de 4 a 6%, comparado com 2 a 4% na população geral. A politerapia é mais lesiva, especialmente se o ácido valpróico e a hidantoína fazem parte da associação. Para as pacientes epilépticas clinicamente assintomáticas há dois anos recomenda-se a suspensão da drogas em uso, porém se apresentam crises, torna-se prudente consultar neurologista para discussão da terapia anticonvulsivante com melhores benefícios e menores efeitos colaterais. Os anestésicos locais e os opióides são largamente utilizados durante a resolução da gestação. A lidocaína utilizada como anestésico por via perineal para episiotomia, na dose fi xa de 400 mg, apresenta alta concentração plasmática materna e alta taxa de transferência placentária no momento do nascimento, que vem alertar para o cuidado no uso de doses repetidas. A bupivacaína administrada por via epidural representa anestésico seguro, apresentando-se na forma racêmica e com transferência placentária em torno de 30%. A fentanila, anestésico opióide, utilizado por via epidural na resolução por cesariana, na dose fi xa de 0,10 mg, apresenta alta taxa de transferência placentária, da ordem de 90%, o que vem alertar para cautela no uso de doses repetidas em analgesia durante o trabalho de parto. PALAVRA-CHAVES:Troca materno-fetal; Anormalidades induzidas por drogas; Gravidez, Anticonvulsivos/efeitos adversos; Anestésicos/efeitos adversos Abstract Pregnant women may depend on the use of medications to minimize the problems caused by preexisting disease, and pregnancy itself can cause situations that compromise the maternal well-being and that require treatment. The obstetrician should be aware of the placental transfer of drugs and of fetal exposure to teratogenic or toxic agents that might compromise the development of the fetus or even its future life.Transport through the placenta involves the movement of molecules between three compartments: maternal blood, cytoplasm of the syncytiotrophoblast, and fetal blood. This movement can occur through the following mechanisms: simple diffusion, facilitated diffusion, active transport, class P, V, F and large ABC family pumps, and endocytosis. With the use of anticonvulsants the incidence of major m...

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Perfusion studies of glyburide transfer across the human placenta: Implications for fetal safety

Cited by 98 publications

References 10 publications

Determination of the Transport Rate of Xenobiotics and Nanomaterials Across the Placenta using the <em>ex vivo</em> Human Placental Perfusion Model

Determination of the Transport Rate of Xenobiotics and Nanomaterials Across the Placenta using the <em>ex vivo</em> Human Placental Perfusion Model

The treatment of Hodgkin's and non-Hodgkin's lymphoma in pregnancy

Transferência placentária de drogas

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