Stage-specific distribution of P-glycoprotein in first-trimester and full-term human placenta

MacFarland, A.K.; Abramovich, D. R.; Ewen, S. W. B.; Pearson, Colin K.

doi:10.1007/bf00160054

Cited by 87 publications

(51 citation statements)

References 19 publications

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“…[88][89][90] MDR1 is expressed in the developing embryo 91) and placenta in a stage-specific manner. 92) Transduction with the human MDR1 gene enables a remarkable expansion of hematopoietic stem cells. 93) MDR1 expression in hematopoietic progenitor cells is dependent on the level of differentiation.…”

Section: Mdr1 In Apoptosis and Immunologymentioning

confidence: 99%

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

173

110

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The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.

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Section: Mdr1 In Apoptosis and Immunologymentioning

confidence: 99%

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Sakaeda

Nakamura

Okumura

2002

Biological & Pharmaceutical Bulletin

173

110

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“…That placental MDR1 is functional in late human pregnancy was questioned by Macfarland et al (1994) who provided some evidence that the efflux mechanism was seemingly active only early in pregnancy and not always was restricted to trophoblasts. However, subsequent studies with human microvillar membranes of term human trophoblasts have indicated an active MDR1 (Nakamura et al, 1997).…”

Section: Evidence For Placental Control Of Permeability and Metabolismmentioning

confidence: 99%

Controlling drug delivery across the placenta

Audus

1999

European Journal of Pharmaceutical Sciences

106

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Abstract:A challenge in modern drug therapy is to develop strategies for safer and more selective targeting of drug delivery in pregnancy. Specifically, approaches are needed that would restrict unnecessary drug exposure to either mother or fetus. There is evidence emerging that indicates the placenta does express natural transport and metabolism processes that function to control drug and nutrient distribution between the mother and fetus. Further, in vitro techniques developed in the past ten years now provide some of the tools necessary to elucidate transport and metabolism processes typical of the human placenta. As a consequence, pharmaceutical scientists are in a position to contribute significantly to the design and development of drugs for pregnancy. Controlling drug delivery across the placenta: A commentary. Eur. J. Pharm. Sci. 8, 161-165. PMID: 10379038. Publisher's official version: http://dx

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“…High levels of P-gp have been detected in human and murine syncytiotrophoblast layers, which are the crucial parts of the hemochorial placental barrier (Cordon-Cardo et al, 1990;Sugawara, 1990;Bremer et al, 1992;Trezise et al, 1992;MacFarland et al, 1994;Nakamura et al, 1997;Lankas et al, 1998;Myloma et al, 1999;Smit et al, 1999;Ushigome et al, 2000;Tanabe et al, 2001). P-gp has been demonstrated to be integrated in the microvillous membrane of the human syncytiotropho-blast that faces directly maternal blood (MacFarland et al, 1994;Ushigome et al, 2000). Transport activity of P-gp in the placental barrier has been examined both in vivo and in vitro (Audus, 1999).…”

mentioning

confidence: 99%

Examination of the Functional Activity of P-glycoprotein in the Rat Placental Barrier Using Rhodamine 123

Pávek

Štaud²,

Fendrich³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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Rhodamine 123 (Rho123), a model substrate of P-glycoprotein (P-gp), was used to evaluate the functional activity of P-gp efflux transporter in the rat placental barrier. The dually perfused rat-term placenta method was used. In our experiments, the materno-fetal transplacental passage of Rho123 did not meet the criteria of the first-order pharmacokinetics, suggesting an involvement of transporter-mediated process. Inhibitors of P-gp, such as [3Ј-keto-Bmt 1 ]-[Val 2 ]-cyclosporine (PSC833), cyclosporine (CsA), quinidine, and chlorpromazine, increased significantly the materno-fetal transplacental passage of Rho123 in the experiments under steady-state conditions. On the other hand, PSC833, CsA, and quinidine decreased the feto-maternal passage of Rho123. Similarly, in the experiments carried out under nonsteady-state conditions, CsA accelerated the passage of Rho123 in the materno-fetal direction and decreased its passage in the opposite direction. Feto-maternal transplacental clearances of Rho123 were found to be considerably higher than those in the materno-fetal course. Potent P-gp inhibitors, such as PSC833 or CsA, partially canceled the asymmetry. Negligible metabolism of Rho123 into its major demethylated metabolite rhodamine 110 was observed in the rat placenta. Expression of P-gp genes was detected using immunohistochemical, Western blotting, and reverse transcription-polymerase chain reaction methods preferentially in the second rat syncytiotrophoblast layer. In conclusion, these data suggest that P-gp limits the entry of Rho123 into fetuses and at the same time it accelerates the feto-maternal elimination of the model compound. Therefore, it seems plausible that pharmacokinetics of xenobiotics in the rat placental barrier could be controlled by P-gp in both directions.

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Stage-specific distribution of P-glycoprotein in first-trimester and full-term human placenta

Cited by 87 publications

References 19 publications

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

MDR1 Genotype-Related Pharmacokinetics and Pharmacodynamics.

Controlling drug delivery across the placenta

Examination of the Functional Activity of P-glycoprotein in the Rat Placental Barrier Using Rhodamine 123

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