Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure

Smit, Johan W.; Huisman, Maarten T.; Tellingen, Olaf van; Wiltshire, Hugh; Schinkel, Alfred H.

doi:10.1172/jci7963

Cited by 321 publications

(198 citation statements)

References 36 publications

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“…Embryos of transgenic mice lacking PGP accumulate 5-fold-higher levels of toxic compounds administered to the mothers than their normal, PGPexpressing counterparts. A similar increase in fetal toxicant accumulation is seen in normal mice that are fed drugs that block the PGP activity (24).…”

Section: Protective Strategies Integral To Developmental Programsmentioning

confidence: 62%

“…For instance, because efflux transporters are the primary defense that protects the embryo against chemicals, it seems prudent to screen compounds to which embryos could be exposed to determine whether the chemicals are cell-permeable and are substrates of the efflux transporters. Chemicals that are permeable, but not substrates, would be predicted to have unrestricted access to embryos (24).…”

Section: Predictive Value Of Understanding Embryo Defensesmentioning

confidence: 99%

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Embryo stability and vulnerability in an always changing world

Hamdoun

Epel

2007

Proc. Natl. Acad. Sci. U.S.A.

318

266

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Contrary to the view that embryos and larvae are the most fragile stages of life, development is stable under real-world conditions. Early cleavage embryos are prepared for environmental vagaries by having high levels of cellular defenses already present in the egg before fertilization. Later in development, adaptive responses to the environment either buffer stress or produce alternative developmental phenotypes. These buffers, defenses, and alternative pathways set physiological limits for development under expected conditions; teratology occurs when embryos encounter unexpected environmental changes and when stress exceeds these limits. Of concern is that rapid anthropogenic changes to the environment are beyond the range of these protective mechanisms.

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Section: Protective Strategies Integral To Developmental Programsmentioning

confidence: 62%

Section: Predictive Value Of Understanding Embryo Defensesmentioning

confidence: 99%

Embryo stability and vulnerability in an always changing world

Hamdoun

Epel

2007

Proc. Natl. Acad. Sci. U.S.A.

318

266

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“…P-gp is present on the apical membrane of many absorptive epithelial and endothelial cells. Because of its localization and distribution, P-gp limits the oral absorption and bioavailability of PIs across intestine, brain, testis and placenta (Kim et al, 1998;Polli et al, 1999;Smit et al, 1999;Choo et al, 2000;Huisman et al, 2001;Huisman et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Agarwal

Pal

Mitra

2007

International Journal of Pharmaceutics

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Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1 and MDCKII-MRP2 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS. KeywordsMDCKII-MDR1; MDCKII-MRP2; MDCKII-MRP1; MDCKII-Bcrp1; MDCKII-WT; Pglycoprotein (P-gp); multidrug resistance protein (MRP); breast cancer resistance protein (BCRP); Lopinavir (LVR); uptake; transport; permeability; efflux ratio (ER)

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“…In this regard, homozygous ABCB1 knockout mice showed many fold higher transplacental transport of ABCB1 substrates such as digoxin, saquinavir, and paclitaxel compared with wild-type mice. 26 It is possible fetal ABCB1 has a crucial role during the formation of lips and palate by minimizing fetal exposure to potentially fetotoxic substances. Fetal ABCB1 polymorphisms could increase the risk of NSOC by altering ABCB1 expression or activity.…”

Section: Discussionmentioning

confidence: 99%

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations

et al. 2013

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ATP-binding cassette (ABC) proteins in the placenta regulate fetal exposure to xenobiotics. We hypothesized that functional polymorphisms in ABC genes influence risk for non-syndromic oral clefts (NSOC). Both family-based and case-control studies were undertaken to evaluate the association of nine potentially functional single-nucleotide polymorphisms within four ABC genes with risk of NSOC. Peripheral blood DNA from a total of 150 NSOC case-parent trios from Singapore and Taiwan were genotyped, as was cord blood DNA from 189 normal Chinese neonates used as controls. In trios, significant association was observed between the ABCB1 single-nucleotide polymorphisms and NSOC (Po0.05). Only ABCB1 rs1128503 retained significant association after Bonferroni correction (odds ratio (OR) ¼ 2.04; 95% confidence interval (CI) ¼ 1.42-2.98), while rs2032582 and rs1045642 showed nominal significance. Association with rs1128503 was replicated in a case-control analysis comparing NSOC probands with controls (OR ¼ 1.58; 95% CI ¼ 1.12-2.23). A comparison between the mothers of probands and controls showed no evidence of association, suggesting NSOC risk is determined by fetal and not maternal ABCB1 genotype. The two studies produced a combined OR of 1.79 (95% CI ¼ 1.38-2.30). The T-allele at rs1128503 was associated with higher risk. This study thus provides evidence that potentially functional polymorphisms in fetal ABCB1 modulate risk for NSOC, presumably through suboptimal exclusion of xenobiotics at the fetal-maternal interface.

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Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure

Cited by 321 publications

References 36 publications

Embryo stability and vulnerability in an always changing world

Embryo stability and vulnerability in an always changing world

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Fetal polymorphisms at the ABCB1-transporter gene locus are associated with susceptibility to non-syndromic oral cleft malformations

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