Overview of Drug Transporters in Human Placenta

The transport of drugs across the placenta is a point of great importance in pharmacotherapy during pregnancy. However, the knowledge of drug transport in pregnancy is mostly based on experimental clinical data, and the underlying biological mechanisms are not fully understood. In this review, we summarize the current knowledge of drug transporters in the human placenta. We only refer to human data since the placenta demonstrates great diversity among species. In addition, we describe the experimental models that have been used in human placental transport studies and discuss their availability. A better understanding of placental drug transporters will be beneficial for the health of pregnant women who need drug treatment and their fetuses.

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Human placental vitamin B6 (pyridoxal) transport: normal characteristics and effects of ethanol

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1992.262.6.r966 ◽

1992 ◽

Vol 262 (6) ◽

pp. R966-R974 ◽

Cited By ~ 4

Author(s):

S. Schenker ◽

R. F. Johnson ◽

J. D. Mahuren ◽

G. I. Henderson ◽

S. P. Coburn

Keyword(s):

Human Placenta ◽

Binding Sites ◽

Vitamin B6 ◽

Passive Transport ◽

Short Term ◽

Placental Transport ◽

Normal Human ◽

Important Form ◽

Composite Data ◽

In Pregnancy

The aims of this study were to define normal human placental transport of pyridoxal, an important form of vitamin B6 in pregnancy, and to determine the effect of short-term alcohol on this process. Our studies used the isolated single cotyledon from the term placenta. Pyridoxal crossed the human placenta readily in both directions, but the transfer was a little less than half that of antipyrine and was significantly greater in the direction of the fetus. Pyridoxine appeared to have a similar clearance from the maternal compartment as pyridoxal, but transport of intact pyridoxal 5'-phosphate was much smaller. There was no saturable transfer of pyridoxal, and it was not transferred from the maternal to fetal compartments against a concentration gradient. Placental concentration of pyridoxal exceeded both maternal and fetal perfusate pyridoxal concentrations, but this concentration was equal for both perfusion directions. These composite data are most suggestive of passive transport of pyridoxal across the placenta, binding of the vitamin in the placenta as an explanation for its concentration there, and greater phosphorylation of pyridoxal in the placenta when the compound is transferred in the fetal direction, possibly displacing pyridoxal from its binding sites and permitting its greater release into the fetal compartment. Alcohol, 400-250 mg/dl over 2.5 h, inhibited the transport of pyridoxal from the maternal to fetal compartments by approximately 42% (P = 0.03) and resulted in a lower transfer of pyridoxal 5'-phosphate into the fetal perfusate (P = 0.02).

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Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms

10.22203/ecm.v021a31 ◽

2011 ◽

Vol 21 ◽

pp. 407-429 ◽

Cited By ~ 282

Author(s):

AMC Barradas ◽

◽

H Yuan ◽

CA van Blitterswijk ◽

P Habibovic

Keyword(s):

Current Knowledge ◽

Experimental Models ◽

Biological Mechanisms

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Pharmacokinetics, Placental and Breast Milk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV

Current Pharmaceutical Design ◽

10.2174/1381612825666190320162507 ◽

2019 ◽

Vol 25 (5) ◽

pp. 556-576 ◽

Cited By ~ 3

Author(s):

E.M. Hodel ◽

C. Marzolini ◽

C. Waitt ◽

N. Rakhmanina

Keyword(s):

Breast Milk ◽

Protease Inhibitors ◽

Drug Class ◽

Drug Transporters ◽

Maternal Plasma ◽

Antiretroviral Drugs ◽

Physiological Changes ◽

Women Living With Hiv ◽

Living With Hiv ◽

In Pregnancy

Background:Remarkable progress has been achieved in the identification of HIV infection in pregnant women and in the prevention of vertical HIV transmission through maternal antiretroviral treatment (ART) and neonatal antiretroviral drug (ARV) prophylaxis in the last two decades. Millions of women globally are receiving combination ART throughout pregnancy and breastfeeding, periods associated with significant biological and physiological changes affecting the pharmacokinetics (PK) and pharmacodynamics (PD) of ARVs. The objective of this review was to summarize currently available knowledge on the PK of ARVs during pregnancy and transport of maternal ARVs through the placenta and into the breast milk. We also summarized main safety considerations for in utero and breast milk ARVs exposures in infants.Methods:We conducted a review of the pharmacological profiles of ARVs in pregnancy and during breastfeeding obtained from published clinical studies. Selected maternal PK studies used a relatively rich sampling approach at each ante- and postnatal sampling time point. For placental and breast milk transport of ARVs, we selected the studies that provided ratios of maternal to the cord (M:C) plasma and breast milk to maternal plasma (M:P) concentrations, respectively.Results:We provide an overview of the physiological changes during pregnancy and their effect on the PK parameters of ARVs by drug class in pregnancy, which were gathered from 45 published studies. The PK changes during pregnancy affect the dosing of several protease inhibitors during pregnancy and limit the use of several ARVs, including three single tablet regimens with integrase inhibitors or protease inhibitors co-formulated with cobicistat due to suboptimal exposures. We further analysed the currently available data on the mechanism of the transport of ARVs from maternal plasma across the placenta and into the breast milk and summarized the effect of pregnancy on placental and of breastfeeding on mammal gland drug transporters, as well as physicochemical properties, C:M and M:P ratios of individual ARVs by drug class. Finally, we discussed the major safety issues of fetal and infant exposure to maternal ARVs.Conclusions:Available pharmacological data provide evidence that physiological changes during pregnancy affect maternal, and consequently, fetal ARV exposure. Limited available data suggest that the expression of drug transporters may vary throughout pregnancy and breastfeeding thereby possibly impacting the amount of ARV crossing the placenta and secreted into the breast milk. The drug transporter’s role in the fetal/child exposure to maternal ARVs needs to be better understood. Our analysis underscores the need for more pharmacological studies with innovative study design, sparse PK sampling, improved study data reporting and PK modelling in pregnant and breastfeeding women living with HIV to optimize their treatment choices and maternal and child health outcomes.

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Experimental Rodent Models of Vascular Dementia: A Systematic Review

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666210108123438 ◽

2021 ◽

Vol 19 ◽

Author(s):

Nidhi Tiwari ◽

Jyoti Upadhyay ◽

Mohd Nazam Ansari ◽

Syed Shadab Raza ◽

Wasim Ahmad ◽

...

Keyword(s):

Vascular Dementia ◽

Small Vessel Disease ◽

Current Knowledge ◽

Vascular Cognitive Impairment ◽

Experimental Models ◽

New Drugs ◽

Amyloid Angiopathy ◽

Vessel Disease ◽

The Brain ◽

Large Vessel Disease

: Vascular dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of vascular cognitive impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small vessel disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and cerebral amyloid angiopathy (CAA),which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

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Disparities in Health Between Black and White Americans: Current Knowledge and Directions for Future Research

The Oxford Handbook of Integrative Health Science ◽

10.1093/oxfordhb/9780190676384.013.33 ◽

2018 ◽

pp. 456-478

Author(s):

Thomas E. Fuller-Rowell ◽

David S. Curtis ◽

Adrienne M. Duke

Keyword(s):

Health Disparities ◽

Current Knowledge ◽

Public Investment ◽

The United States ◽

Future Research ◽

Sociocultural Factors ◽

White Americans ◽

Biological Mechanisms ◽

Black And White ◽

Racial Ethnic

Conceptual frameworks for racial/ethnic health disparities are abundant, but many have received insufficient empirical attention. As a result, there are substantial gaps in scientific knowledge and a range of untested hypotheses. Particularly lacking is specificity in behavioral and biological mechanisms for such disparities and their underlying social determinants. Alongside lack of political will and public investment, insufficient clarity in mechanisms has stymied efforts to address racial health disparities. Capitalizing on emergent findings from the Midlife in the United States (MIDUS) study and other longitudinal studies of aging, this chapter evaluates research on health disparities between black and white US adults. Attention is given to candidate behavioral and biological mechanisms as precursors to group differences in morbidity and mortality and to environmental and sociocultural factors that may underlie these mechanisms. Future research topics are discussed, emphasizing those that offer promise with respect to illuminating practical solutions to racial/ethnic health disparities.

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Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Cells ◽

10.3390/cells10030506 ◽

2021 ◽

Vol 10 (3) ◽

pp. 506

Author(s):

Loris Zamai

Keyword(s):

Chelating Agents ◽

Ethylenediaminetetraacetic Acid ◽

Current Knowledge ◽

Clinical Manifestations ◽

Renin Angiotensin System ◽

Experimental Models ◽

Zinc Metalloprotease ◽

Previous Hypothesis ◽

Zinc Metalloproteases

The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

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Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Cells ◽

10.3390/cells10081844 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1844

Author(s):

Maria Luísa da Silveira Hahmeyer ◽

José Eduardo da Silva-Santos

Keyword(s):

Septic Shock ◽

Actin Polymerization ◽

Current Knowledge ◽

Cecal Ligation ◽

Experimental Models ◽

Rho Proteins ◽

Growing Cell ◽

Sepsis And Septic Shock

Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models.

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Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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Lack of effect of cocaine on lysine and alanine uptake in human placental villi or transfer in perfused human placenta

Reproduction Fertility and Development ◽

10.1071/rd9951495 ◽

1995 ◽

Vol 7 (6) ◽

pp. 1495 ◽

Cited By ~ 3

Author(s):

RB Krishna ◽

M Levitz ◽

J Dancis

Keyword(s):

Amino Acid ◽

Human Placenta ◽

Clinical Situation ◽

Experimental Models ◽

Antipyrine Clearance ◽

Placental Villi ◽

Glucose Clearance ◽

Index Ratio ◽

Transfer Index

The effect of cocaine on lysine and alanine uptake in human placental villi and transfer across the dually perfused placenta was studied. Uptake (in terms of the intracellular to extracellular distribution ratio) of alanine and lysine was 2.81 +/- 0.30 (n = 5) and 1.45 +/- 0.24 (n = 5) respectively and was unaffected by cocaine (50-500 ng mL(-1) in the incubation medium. In the dually perfused placenta, the clearance index (ratio of amino acid to antipyrine clearance) was 0.35 +/- 0.03 and 0.30 +/- 0.05 and the transfer index (ratio of amino acid to L-glucose clearance) was 2.20 +/- 0.07 and 1.89 +/- 0.29 for lysine and alanine respectively. Cocaine at concentrations of 100 ng mL(-1) or 250 ng mL(-1) had no effect on the clearance of either amino acid. The results of this study indicate that concentrations of cocaine likely to be encountered in vivo do not affect uptake of lysine or alanine by placental villi or transfer across the perfused placental lobule, in contrast with the report that cocaine reduces uptake of alanine by placental vesicles. Experimental models must be critically evaluated before accepting the results as pertinent to a clinical situation.

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