Human placental transport of cimetidine.

Schenker, Steven; Dicke, Jeffrey M.; Johnson, Raymond F.; Mor, L.; Henderson, George I.

doi:10.1172/jci113222

Cited by 49 publications

(17 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, K is the slope of drug appearance in the recipient reservoir, V is the recipient perfusate volume, and C is the mean drug concentration in the donor circuit. This equation is appropriate for compounds that do not reach equilibrium in the model (Schenker et al, 1987). All graphical and statistical analyses were performed using GraphPad Prism 3.0.…”

Section: Methodsmentioning

confidence: 99%

Human Placental Glucuronidation and Transport of 3′azido-3′-Deoxythymidine and Uridine Diphosphate Glucuronic Acid

Collier¹,

Keelan²,

Zijl³

et al. 2004

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:These studies were performed to characterize the contribution of the uridine diphosphate glucuronosyltransferase (UGT) enzymes to the clearance of 3-azido-3-deoxythymidine (AZT) in vivo and to assess the regulation of UGT activity [including the disposition of the cofactor uridine diphosphate glucuronic acid (UDPGA)] in the placenta. Transport of AZT and the cofactor UDPGA across the human placenta and the glucuronidation capacity of the placenta for AZT were assessed using a human placental cell line (JEG-3), primary cultures of villous term placenta, placental subcellular fractions, and a recirculating perfusion model. Glucuronidation of AZT was consistently observed at approximately 2% of the dose administered. High levels of AZT in cultured primary placental cells and lines caused autoinhibition of AZT metabolism. AZT crossed the perfused placenta in a bidirectional fashion and was at equilibrium after 3 h, whereas the AZT-glucuronide metabolite was excreted preferentially into the maternal compartment. In contrast, UDPGA (10 M) was rapidly transferred from the maternal to the fetal circulation, being complete after 4 h of perfusion. AZT is transported and glucuronidated by the human placenta, but that placental metabolism of the drug is not significant for whole-body clearance. Likewise therapeutic failure of AZT (5-15%) is not due to placental obstruction of drug passage. Finally, the activity of the UGT enzymes in the placenta is not rate-limited by the supply of UDPGA cofactor, whereas the preferential transport of UDPGA toward the fetus observed here may indicate a role in fetal development.

show abstract

Section: Methodsmentioning

confidence: 99%

Human Placental Glucuronidation and Transport of 3′azido-3′-Deoxythymidine and Uridine Diphosphate Glucuronic Acid

Collier¹,

Keelan²,

Zijl³

et al. 2004

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…In several experiments antipyrine and 3H-~-glucose were used as reference molecules. Antipyrine, a readily diffusable lipophillic substance, is added to the maternal perfusate at a concentration of 12 mg/100 mL, a level at which no antipyrine metabolites are detected (43). Antipyrine concentrations in maternal and fetal perfusates are used to calculate clearance and an exchange index, which references the exchange of any compound in question to the clearance of antipyrine, for taurine.…”

Section: Placental Perfusionmentioning

confidence: 99%

Taurine Transport in the in Vitro Perfused Human Placenta

et al. 1990

View full text Add to dashboard Cite

ABSTRACT. Taurine, required by the fetus for nutrition and neurological development, is inadequately synthesized by the fetus and substantial quantities of the amino acid are supplied by the mother. Maternal to fetal unidirectional taurine transport was studied in in vitro perfused human placentae from normal term deliveries. To determine whether the placenta can achieve and maintain a chemical gradient for taurine, recirculating equimolar maternal and fetal perfusions were performed. The ratio of fetallmaternal taurine concentration increased over 75 min and was maintained at 1.38 f 0.14 (SEM) through 2.25 h (n = 6).To determine the rate of taurine transport against a concentration gradient, flux was determined with maternal taurine constant at 50 pM whereas the fetal taurine concentration varied from 0 to 500 pM in a nonrecirculating system (n = 5). Despite increasing the chemical gradient tenfold, taurine was transported at a constant rate of 1.75 f 0.75 (SEM) nmol/min/g. Nonrecirculating perfusions were performed with B-alanine (n = 13) and hypotaurine

show abstract

“…In the present study, cimetidine was used to comprehensively describe the role of Bcrp in maternal-to-fetal and fetalto-maternal transport. Cimetidine was chosen as a model substrate for its convenient properties; it is a BCRP substrate that is not recognized by human P-gp , it weakly binds to plasma proteins, and its biotransformation by placental enzymes is negligible (Schenker et al, 1987). In addition, cimetidine passive diffusion through biological membranes is delayed by its physical-chemical properties as shown in transepithelial passage or placental transport (Ching et al, 1987;Schenker et al, 1987); this seems to be an important feature to study substrate interactions with an efflux transporter (Eytan et al, 1996;Lentz et al, 2000).…”

mentioning

confidence: 99%

“…In a follow-up study, the authors suggested that an active transporter from the fetal to the maternal circulation might be responsible for this discrepancy (Ching et al, 1985). In contrast, when investigated in the dually perfused human placenta, two papers concluded that transport of cimetidine was very slow and occurred by passive diffusion with lack of saturation kinetics (Ching et al, 1987;Schenker et al, 1987). These contrasting findings might be explained by interspecies differences; however, one has to realize that these studies were performed before efflux transporters were discovered and described, with limited range of cimetidine concentrations, and without the option to use appropriate inhibitors.…”

mentioning

confidence: 99%

Expression and Transport Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Dually Perfused Rat Placenta and HRP-1 Cell Line

Štaud

Vacková²,

Pospěchová³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Breast cancer resistance protein (BCRP/ABCG2) is a member of the ATP-binding cassette transporter family that recognizes a variety of chemically unrelated compounds. Its expression has been revealed in many mammal tissues, including placenta. The purpose of this study was to describe its role in transplacental pharmacokinetics using rat placental HRP-1 cell line and dually perfused rat placenta. In HRP-1 cells, expression of Bcrp, but not P-glycoprotein, was revealed at mRNA and protein levels. Cell accumulation studies confirmed Bcrp-dependent uptake of BODIPY FL prazosin. In the placental perfusion studies, a pharmacokinetic model was applied to distinguish between passive and Bcrp-mediated transplacental passage of cimetidine as a model substrate. Bcrp was shown to act in a concentration-dependent manner and to hinder maternal-tofetal transport of the drug. Fetal-to-maternal clearance of cimetidine was found to be 25 times higher than that in the opposite direction; this asymmetry was partly eliminated by BCRP inhibitors fumitremorgin C (2 M) or N- (4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918; 2 M) and abolished at high cimetidine concentrations (1000 M). When fetal perfusate was recirculated, Bcrp was found to actively remove cimetidine from the fetal compartment to the maternal compartment even against a concentration gradient and to establish a 2-fold maternal-to-fetal concentration ratio. Based on our results, we propose a two-level defensive role of Bcrp in the rat placenta in which the transporter 1) reduces passage of its substrates from mother to fetus but also 2) removes the drug already present in the fetal circulation.Placenta is an organ that brings maternal and fetal blood circulations into proximity, allowing mutual interchange of nutrients and waste products. Conversely, placenta forms a barrier to protect the fetus against harmful endo-and exogenous compounds from maternal circulation. As a barrier, the human and rodent placenta had for long been supposed to present only a mechanical obstruction formed by fetal endothelia, basal membranes, and syncytiotrophoblast. However, over the past two decades, a variety of metabolizing enzymes and drug efflux transporters of the ATP-binding cassette (ABC) transporter family have been localized in placental trophoblast (Marin et al., 2004;Syme et al., 2004). These proteins are thought to strengthen, in an active and capacitylimited manner, placental barrier role and help in protecting the fetus.Drug efflux transporters of the ABC family are membraneembedded proteins that limit intracellular concentration of substrates by pumping them out of cell through an active, energy-dependent mechanism (Schinkel and Jonker, 2003). The most intensively studied drug efflux transporters to date have been P-glycoprotein (P-gp; ABCB1), breast cancer resistance protein (BCRP; ABCG2) and multidrug resistance-associated proteins 1 and 2 (ABCC1 and ABCC2), all of which were found t...

show abstract

Human placental transport of cimetidine.

Cited by 49 publications

References 25 publications

Human Placental Glucuronidation and Transport of 3′azido-3′-Deoxythymidine and Uridine Diphosphate Glucuronic Acid

Human Placental Glucuronidation and Transport of 3′azido-3′-Deoxythymidine and Uridine Diphosphate Glucuronic Acid

Taurine Transport in the in Vitro Perfused Human Placenta

Expression and Transport Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Dually Perfused Rat Placenta and HRP-1 Cell Line

Contact Info

Product

Resources

About