Misoprostol-Induced Fever and Genetic Polymorphisms in Drug Transporters
 SLCO1B1
 and
 ABCC4
 in Women of Latin American and European Ancestry

Alfirevic, Ana; Durocher, Jill; Elati, A; León, Wilfrido; Dickens, David; Rädisch, Steffen; Box, Helen; Siccardi, Marco; Curley, Paul; Xinarianos, George; Ardeshana, Arjun; Owen, Andrew; Zhang, J Eunice; Pirmohamed, Munir; Alfirević, Z̄arko; Weeks, Andrew; Winikoff, Beverly

doi:10.2217/pgs.15.53

Cited by 14 publications

(16 citation statements)

References 45 publications

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“…injection of MRP4 substrate antibiotics, cefmetazol and cefazolin, reduced elimination rate of pre-injected PGE 2 to the brain. 72) However, other MRP4 substrate drugs such as cefotaxime and ketoprofen did not affect the elimination rate. Because cefotaxime and ketoprofen are poorly permeable to the BBB, their intracellular concentration might not be sufficient to inhibit MRP4 function in brain endothelial cells.…”

Section: Mouse Abcc4mentioning

confidence: 94%

“…Mrp4 MOATB N.D. 72) Br, 20,66) at the luminal membranes of rat primary cultured cerebral endothelial cells. 29) OATP2A1 protein is also expressed in blood vessels at the middle frontal gyrus of human brains.…”

Section: Mouse Abcc4mentioning

confidence: 99%

“…Because cefotaxime and ketoprofen are poorly permeable to the BBB, their intracellular concentration might not be sufficient to inhibit MRP4 function in brain endothelial cells. 72) In humans, misoprostol, a PGE 1 analogue, which can cause high fevers, is a substrate of MRP4. A non-synonymous single nucleotide polymorphism of MRP4 (rs11568658, G187W), which shows reduced transport activity, has been reported associated with misoprostolinduced fever.…”

Section: Mouse Abcc4mentioning

confidence: 99%

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Membrane Transporters Contributing to PGE2 Distribution in Central Nervous System

Nakamura

Nakanishi

Tamai

2018

Biological & Pharmaceutical Bulletin

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Prostaglandin (PG) E is a well-established lipid mediator that plays a role in diverse functions and diseases of the brain. Cyclooxygenase and PGE synthase have been extensively studied as molecular determinants of extracellular concentration of PGE near prostanoid E receptors since the brain has limited capacity of PG metabolism. There is accumulating evidence that several members of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate PGE distribution in brain capillary endothelial cells, choroid plexus (CP) and arachnoid epithelium, and different parenchyma cells such as neuronal and glial cells. These transporters may mediate entry and exit of PGE at blood-brain and blood-cerebrospinal fluid boundaries, resulting in brain distribution of PGE. However, their roles in neuroinflammation and disease progression remain unclear. In this review, current knowledge on transporters involved in brain distribution of PGE is summarized, and especially, potentials of organic anion transporting polypeptide (OATP) and organic anion transporter (OAT) family members are discussed as molecular determinants of PGE concentration in the brain.

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Section: Mouse Abcc4mentioning

confidence: 94%

Section: Mouse Abcc4mentioning

confidence: 99%

Section: Mouse Abcc4mentioning

confidence: 99%

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Membrane Transporters Contributing to PGE2 Distribution in Central Nervous System

Nakamura

Nakanishi

Tamai

2018

Biological & Pharmaceutical Bulletin

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“…This study investigated differential uptake of EFV SDNs relative to an aqueous solution in the human cerebral microvessel endothelial cells (hCMEC)/D3 cell line in vitro, which is derived from human microvascular brain endothelial cells (Alfirevic et al, ; Dickens et al, ; Weksler et al, ). The hCMEC/D3 was selected for its frequent application as an in vitro model and characterisation as an immortalised BBB cell line.…”

Section: Introductionmentioning

confidence: 99%

“…Macropinocytosis is typically involved in uptake of larger particles (<2 μM), whereas clathrin-mediated (<300 nm) and caveolae-mediated (<80 nm) endocytosis may predominate for smaller particles (Canton and Battaglia, 2012). This study investigated differential uptake of EFV SDNs relative to an aqueous solution in the human cerebral microvessel endothelial cells (hCMEC)/D3 cell line in vitro, which is derived from human microvascular brain endothelial cells (Alfirevic et al, 2015;Dickens et al, 2012;Weksler et al, 2013). The hCMEC/D3 was selected for its frequent application as an in vitro model and characterisation as an immortalised BBB cell line.…”

Section: Introductionmentioning

confidence: 99%

In vitro characterisation of solid drug nanoparticle compositions of efavirenz in a brain endothelium cell line

Curley

Giardiello

Liptrott

et al. 2017

J of Interdiscip Nanomed

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The antiretroviral drug efavirenz displays many desirable pharmacokinetic properties such as a long half-life enabling once daily dosing but suffers from central nervous system safety issues. Various nanotechnologies have been explored to mitigate some of the limitations with efavirenz. While there has been progress in increasing the bioavailability, there has been no attempt to assess the impact of increased exposure to efavirenz on central nervous system safety. The uptake of aqueous and solid drug nanoparticle (SDN) formulations of efavirenz was assessed in the human cerebral microvessel endothelial cells/D3 brain endothelial cell line. The mechanisms of uptake were probed using a panel of transport and endocytosis inhibitors. The cellular accumulation of an efavirenz aqueous solution was significantly reduced by amantadine, but this was not observed with SDNs. The uptake of efavirenz SDNs was reduced by dynasore, but concentrations of the efavirenz aqueous solution were not affected. These data indicate that efavirenz is a substrate for transporters in brain endothelial cells (amantadine is an inhibitor of organic cation transporters 1 and 2), and formation of SDNs may bypass this interaction in favour of a mechanism involving dynamin-mediated endocytosis.

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Drug Routes of Excretion

2017

Oral Bioavailability Assessment

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Misoprostol-Induced Fever and Genetic Polymorphisms in Drug Transporters SLCO1B1 and ABCC4 in Women of Latin American and European Ancestry

Abstract: Genetic variability in ABCC4 may contribute to misoprostol-induced fever in pregnant women. Original submitted 21 January 2015; Revision submitted 24 April 2015.

Cited by 14 publications

References 45 publications

Membrane Transporters Contributing to PGE<sub>2</sub> Distribution in Central Nervous System

Membrane Transporters Contributing to PGE<sub>2</sub> Distribution in Central Nervous System

In vitro characterisation of solid drug nanoparticle compositions of efavirenz in a brain endothelium cell line

Drug Routes of Excretion

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