An effective PBPK model predicting dissolved drug transfer from a representative nasal cavity to the blood stream

Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.

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Interspecies Dose Extrapolation for Inhaled Dimethyl Sulfate: A PBPK Model-Based Analysis using Nasal Cavity N7-Methylguanine Adducts

Inhalation Toxicology ◽

10.1080/08958370490464562 ◽

2004 ◽

Vol 16 (9) ◽

pp. 593-605 ◽

Cited By ~ 9

Author(s):

Ramesh Sarangapani ◽

Justin G. Teeguarden ◽

P. Robinan Gentry ◽

Harvey J. Clewell ◽

Hugh A. Barton ◽

...

Keyword(s):

Nasal Cavity ◽

Pbpk Model ◽

Dimethyl Sulfate ◽

Model Based ◽

Model Based Analysis

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Processing of human melanoma cells for correlative TEM, LVSEM, and LM

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100084831 ◽

1991 ◽

Vol 49 ◽

pp. 106-107

Author(s):

Marek Malecki ◽

J. Victor Small ◽

James Pawley

Keyword(s):

Electron Microscopy ◽

Low Voltage ◽

Fluorescent Microscopy ◽

Blood Stream ◽

Surface Topology ◽

Integrin Receptors ◽

Transmission Electron ◽

Develop Technology ◽

Voltage Scanning ◽

Mechanisms Of Adhesion

The relative roles of adhesion and locomotion in malignancy have yet to be clearly established. In a tumor, subpopulations of cells may be recognized according to their capacity to invade neighbouring tissue,or to enter the blood stream and metastasize. The mechanisms of adhesion and locomotion are themselves tightly linked to the cytoskeletal apparatus and cell surface topology, including expression of integrin receptors. In our studies on melanomas with Fluorescent Microscopy (FM) and Cell Sorter(FACS), we noticed that cells in cultures derived from metastases had more numerous actin bundles, then cells from primary foci. Following this track, we attempted to develop technology allowing to compare ultrastructure of these cells using correlative Transmission Electron Microscopy(TEM) and Low Voltage Scanning Electron Microscopy(LVSEM).

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Ultrastructural studies on the interaction of haemophilus influenzae with human endothelial cells in vitro

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010016073x ◽

1990 ◽

Vol 48 (3) ◽

pp. 636-637

Author(s):

D.J.P. Ferguson ◽

M. Virji ◽

H. Kayhty ◽

E.R. Moxon

Keyword(s):

Endothelial Cells ◽

Haemophilus Influenzae ◽

Intercellular Junctions ◽

Blood Stream ◽

Ultrastructural Studies ◽

Endothelial Barriers ◽

Serotype B ◽

Meningitis In Children ◽

Respiratory Epithelial

Haemophilus influenzae is a human pathogen which causes meningitis in children. Systemic H. influenzae infection is largely confined to encapsulated serotype b organisms and is a major cause of meningitis in the U.K. and elsewhere. However, the pathogenesis of the disease is still poorly understood. Studies in the infant rat model, in which intranasal challenge results in bacteraemia, have shown that H. influenzae enters submucosal tissues and disseminates to the blood stream within minutes. The rapidity of these events suggests that H. influenzae penetrates both respiratory epithelial and endothelial barriers with great efficiency. It is not known whether the bacteria penetrate via the intercellular junctions, are translocated within the cells or carried across the cellular barrier in 'trojan horse' fashion within phagocytes. In the present studies, we have challenged cultured human umbilical cord_vein endothelial cells (HUVECs) with both capsulated (b+) and capsule-deficient (b-) isogenic variants of one strain of H. influenzae in order to investigate the interaction between the bacteria and HUVEC and the effect of the capsule.

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Use of Antimicrobial Lock Therapy for the Treatment of Central Line-Related Blood-Stream Infections: A Case Series

10.1055/s-0038-1647089 ◽

2018 ◽

Author(s):

F. Piersigilli ◽

C. Auriti ◽

I. Bersani ◽

F. Campi ◽

I. Savarese ◽

...

Keyword(s):

Case Series ◽

Blood Stream ◽

Central Line ◽

Blood Stream Infections ◽

Lock Therapy

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The Turnover in Normal Dogs of Prothrombin and Its Fragments; Effect of Induced Intravascular Coagulation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1666892 ◽

1979 ◽

Vol 42 (02) ◽

pp. 548-555 ◽

Cited By ~ 2

Author(s):

Charles A Owen ◽

Kenneth G Mann ◽

Frederic C McDuffie

Keyword(s):

Close Agreement ◽

Blood Stream ◽

The Other ◽

Normal Adult ◽

Capillary Barrier ◽

Prothrombin Fragment ◽

Intravascular Coagulation ◽

Dog Brain

SummaryWhen 125I-labeled canine prothrombin was given to normal adult dogs intravenously, it was calculated that 240% of the plasma prothrombin crossed the capillary barrier per day, 410% of the interstitial prothrombin returned to the blood stream daily, and 79% of the plasmatic prothrombin was catabolized per day. These data are in close agreement with those observed for bovine prothrombin in calves by Takeda (1970).When derived from normal dog prothrombin, prethrombin-1 is a mixture of 2 polypeptides, one larger than the other, and both present in about equal amounts. The longer peptide, “prethrombin-1-long,” was catabolized twice as fast as prothrombin, and the shorter, “prethrombin-1-short,” 4 times faster. Prothrombin fragment-1 was catabolized by the normal dog still more rapidly.The catabolism of prothrombin was not accelerated in 3 dogs receiving continuous infusions of a thromboplastic emulsion of dog brain. Nor was the level of prothrombin in their plasma remarkably altered.

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