scholarly journals Pulmonary Pharmacokinetics of Oseltamivir Carboxylate in Rats after Nebulization or Intravenous Administration of Its Prodrug, Oseltamivir Phosphate

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Romain Carrez ◽  
Julien Brillault ◽  
Nicolas Grégoire ◽  
Isabelle Lamarche ◽  
Julian Laroche ◽  
...  
Keyword(s):  
Intravenous Administration ◽  
Good Option ◽  
Infection Site ◽  
Oseltamivir Carboxylate ◽  
High Exposure ◽  
Active Moiety ◽  
Oseltamivir Phosphate

ABSTRACT The aim of this study was to investigate the pharmacokinetics of oseltamivir phosphate, a prodrug, and its active moiety in plasma and lung after its nebulization and intravenous administration in rats. Only 2% of prodrug was converted into active moiety presystematically, attesting to a low advantage of oseltamivir phosphate nebulization, suggesting that oseltamivir phosphate nebulization is not a good option to obtain a high exposure of the active moiety at the infection site within lung.

Pharmacokinetics of oseltamivir phosphate and oseltamivir carboxylate in non-pregnant and pregnant rhesus monkeys

2020 ◽  
Vol 112 ◽  
pp. 104569
Author(s):  
Lucie Loukotková ◽  
Mallikarjuna Basavarajappa ◽  
Annie Lumen ◽  
Rosemary Roberts ◽  
Donald Mattison ◽  
...  
Keyword(s):  
Rhesus Monkeys ◽  
Oseltamivir Carboxylate ◽  
Oseltamivir Phosphate

Reductive amination assistance for quantification of oseltamivir phosphate and oseltamivir carboxylate by HPLC-MS/MS

2018 ◽  
Vol 1087-1088 ◽  
pp. 23-28 ◽  
Author(s):  
Mei-Fang Huang ◽  
Yi-Reng Lin ◽  
Yu-Tzu Chang ◽  
Yow-Ling Shiue ◽  
Shih-Shin Liang
Keyword(s):  
Reductive Amination ◽  
Oseltamivir Carboxylate ◽  
Oseltamivir Phosphate

scholarly journals A physiologically-based pharmacokinetic model of oseltamivir phosphate and its carboxylate metabolite for rats and humans

ADMET & DMPK ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 22-43 ◽  
Author(s):  
Guanghua Gao ◽  
Francis Law ◽  
Ricky Ngok Shun Wong ◽  
Nai Ki Mak ◽  
Mildred Sze Ming Yang
Keyword(s):  
Influenza Virus ◽  
Pbpk Model ◽  
Viral Agent ◽  
Internal Tissue ◽  
Oseltamivir Carboxylate ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Influenza Virus Neuraminidase ◽  
Oseltamivir Phosphate

Oseltamivir phosphate (OP, Tamiflu®) is a widely used prodrug for the treatment of influenza viral infections. Orally administered OP is rapidly hydrolyzed by the carboxylesterases in animals to oseltamivir carboxylate (OC), a potent influenza virus neuraminidase inhibitor. The goals of this study were to develop and validate a physiologically-based pharmacokinetic (PBPK) model of OP/OC in rats and humans, and to predict the internal tissue doses for OP and OC in humans after receiving OP orally. To this end, a PBPK model of OP/OC was first developed in the rat, which was then scaled up to humans by replacing the physiological and biochemical parameters with human-specific values. The proposed PBPK model consisted of an OP and an OC sub-models each containing nine first-order, flow-limited tissue/organ compartments. OP metabolism to OC was assumed to carry out mainly by hepatic carboxylesterases although extra-hepatic metabolism also occurred especially in the plasma. The PBPK model was developed and validated by experimental data from our laboratories and from the literature. The proposed PBPK model accurately predicted the pharmacokinetic behavior of OP and OC in humans and rats after receiving a single or multiple doses of OP orally or an OC dose i.v. The PBPK model was used to predict the internal tissue doses of OP and OC in a hypothetical human after receiving the recommended dose of 75 mg/kg OP b.i.d. for 6 days. Steady-state OC concentrations in the plasma and major organs such as the lung and the brain were higher than the minimum in vitro IC50 reported for H1N1 influenza virus neuraminidase, confirming OP is an effective, anti-viral agent. OP side-effects in the gastrointestinal tract and brain of humans were explainable by the tissue doses found in these organs. The PBPK model provides a quantitative tool to evaluate the relationship between an externally applied dose of OP and the internal tissue doses in humans. As such the model can be used to adjust the dose regimens for adult patients in disease states e.g., renal failure and liver damage.

scholarly journals High Levels and Safety of Oseltamivir Carboxylate Plasma Concentrations after Nasogastric Administration in Critically Ill Children in a Pediatric Intensive Care Unit

2010 ◽  
Vol 55 (1) ◽  
pp. 433-435 ◽  
Author(s):  
Carole Giraud ◽  
Sandra Manceau ◽  
Mehdi Oualha ◽  
Hélène Chappuy ◽  
Agnès Mogenet ◽  
...  
Keyword(s):  
Intensive Care ◽  
Plasma Concentrations ◽  
Pediatric Intensive Care ◽  
H1n1 Influenza ◽  
Critically Ill Children ◽  
Oseltamivir Carboxylate ◽  
Influenza Pandemics ◽  
2009 H1n1 ◽  
The Mean ◽  
Oseltamivir Phosphate

ABSTRACTDuring the 2009 H1N1 influenza pandemics, the concentrations of oseltamivir (O) and its active metabolite (oseltamivir carboxylate [OC]) were determined in 11 children (1 month to 16 years of age) admitted to intensive care units for presumed severe H1N1 infection. They received oseltamivir phosphate (OP) nasogastrically at doses between 1.5 and 6.8 mg/kg of body weight. High OC concentrations were found, with a mean level of 678 ± 535 μg/liter. The mean OP concentration was 27 ± 52 μg/liter. No marked side effect was reported.

scholarly journals Detection of Antiviral Drugs Oseltamivir Phosphate and Oseltamivir Carboxylate in Neya River, Osaka, Japan

2010 ◽  
Vol 8 (4) ◽  
pp. 363-372 ◽  
Author(s):  
Ryohei TAKANAMI ◽  
Hiroaki OZAKI ◽  
Rabindra Raj GIRI ◽  
Shogo TANIGUCHI ◽  
Shintaro HAYASHI
Keyword(s):  
Antiviral Drugs ◽  
Oseltamivir Carboxylate ◽  
Oseltamivir Phosphate

scholarly journals The Metabolism and Transplacental Transfer of Oseltamivir in the Ex Vivo Human Model

2008 ◽  
Vol 2008 ◽  
pp. 1-5 ◽  
Author(s):  
Kevin C. Worley ◽  
Scott W. Roberts ◽  
Roger E. Bawdon
Keyword(s):  
Active Metabolite ◽  
Ex Vivo ◽  
Reference Method ◽  
Human Model ◽  
Transplacental Passage ◽  
Oseltamivir Carboxylate ◽  
Ex Vivo Model ◽  
Transplacental Transfer ◽  
Perfusion Studies ◽  
Oseltamivir Phosphate

Oseltamivir phosphate is extensively metabolized in the ex vivo human placenta model, and the transplacental passage of the metabolite oseltamivir carboxylate is incomplete.Objective. To evaluate the metabolism and transplacental transfer of oseltamivir (Tamiflu) in the ex vivo human placental model.Study Design. Perfusion studies were performed in six placentas from term, uncomplicated deliveries. Concentrations of oseltamivir phosphate (OP) that were 5-6 fold, 20–30 fold, and 600–800 fold above the therapeutic peak were tested, as neither OP nor its active metabolite, oseltamivir carboxylate (OC), could be detected at near-therapeutic concentrations. The transplacental transfer and accumulation of OC were assessed using the antipyrine reference method.Results. OP was extensively metabolized to OC. In the 4 placentas with the highest concentration of OP, OC had a mean clearance index of , suggesting that transplacental passage occurs at a relatively low rate. Measurable fetal accumulation occurred in the two placentas with the highest initial concentrations.Conclusions. Oseltamivir phosphate was extensively metabolized in the ex vivo model. Transplacental transfer of the metabolite was incomplete and accumulation was minimal.

5. Inhibitory Potency of Tamiflu Oseltamivir and DANA and their Modified Derivatives on Lipopolysaccharide-Induced Neu1 Sialidase Activity in Live BMA Macrophage Cells

2016 ◽  
Author(s):  
Merry Guo
Keyword(s):  
Cell Signalling ◽  
Side Chain ◽  
Oseltamivir Carboxylate ◽  
Inhibitory Potency ◽  
Sialidase Activity ◽  
Macrophage Cells ◽  
Alkyl Side Chains ◽  
Molecular Patterns ◽  
Neu1 Sialidase ◽  
Oseltamivir Phosphate

Toll-like receptors (TLRs) are a group of ancient receptors found on the surface of cells in our innate immune system. They are responsible for detecting conserved molecules found on pathogenic microbes, called Pathogen Associated Molecular Patterns (PAMP), such as lipopolysaccharide (LPS) molecules on the cell surfaces of Gram-negative bacteria. The activation of TLRs leads to immune responses against the pathogen infection. Although the cell signalling follow the activation of TLRs is well characterized, the initial mechanisms for TLR activation upon detecting PAMPs are not well understood. For the TLR-2,-3 and-4 receptors, we reported that an enzyme called Neu1 sialidase forms a complex with the TLR receptors on the cell surface of naïve and activated macrophages (Amith et al, 2009). Activation of this Neu1 is induced by the binding of TLR ligands, such as LPS, to their respective receptors; a specific sialyl -2,3-linked β-galactosyl residue on the TLR is hydrolyzed by the activated Neu1 enzyme. Neuraminidase inhibitors such as BCX1827, DANA, zanamivir and oseltamivir carboxylate have a limited inhibition of this LPS-induced Neu1 activity in live macrophage cells. In contrast, Tamiflu (oseltamivir phosphate) completely blocked this Neu1 activity. Here, we tested the inhibitory potency of a series of DANA and modified Tamiflu derivatives against the activity of the Neu1 enzyme. The results suggest that the linear alkyl side chains of DANA derivatives may contribute to their increased inhibitory potency on LPS-induced Neu1 activity compared to the derivatives with methyl side chain branches and to the parent DANA compound.

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