scholarly journals Oseltamivir Carboxylate, the Active Metabolite of Oseltamivir Phosphate (Tamiflu), Detected in Sewage Discharge and River Water in Japan

2010 ◽  
Vol 118 (1) ◽  
pp. 103-107 ◽  
Author(s):  
Gopal C. Ghosh ◽  
Norihide Nakada ◽  
Naoyuki Yamashita ◽  
Hiroaki Tanaka
Keyword(s):  
River Water ◽  
Active Metabolite ◽  
Oseltamivir Carboxylate ◽  
Sewage Discharge ◽  
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.

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

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.

scholarly journals Oseltamivir and Oseltamivir Carboxylate Pharmacokinetics in Obese Adults: Dose Modification for Weight Is Not Necessary

2011 ◽  
Vol 55 (12) ◽  
pp. 5640-5645 ◽  
Author(s):  
Manjunath P. Pai ◽  
Thomas P. Lodise
Keyword(s):  
Active Metabolite ◽  
Influenza A ◽  
Systemic Exposure ◽  
Lean Body Weight ◽  
Population Pharmacokinetic ◽  
Class Iii ◽  
Oseltamivir Carboxylate ◽  
Obese Adults ◽  
Time Curve ◽  
Apparent Clearance

ABSTRACTObesity is an independent risk factor for mortality in patients infected with pandemic influenza A virus (H1N1). Given the poor outcomes observed among adult obese patients with H1N1, the dosing of antiviral agents in this population has been questioned, and use of twice the standard oseltamivir dose has been suggested. However, studies evaluating the disposition of oseltamivir and oseltamivir carboxylate (the active metabolite) in the obese population are scant. We evaluated the single-dose and steady-state pharmacokinetics of oseltamivir (75 mg by mouth twice daily) in a cohort of 21 healthy adult volunteers with class III obesity (body mass index [BMI], ≥40 kg/m2). The median (minimum, maximum) age, weight, and BMI were 36 (19, 50) years, 122 (106, 159) kg, and 43.7 (40.0, 54.4) kg/m2, respectively. The population pharmacokinetic exposure profiles of oseltamivir carboxylate (the active metabolite) were comparable between class III obese subjects and nonobese adults (healthy and infected). Similar to previous pharmacokinetic analyses in nonobese subjects, the mean (percent covariance [CV]) area under the concentration-time curve for the dosing interval (AUC0–τ) was 2,621 ng·h/ml (17) for oseltamivir carboxylate. Body size was significantly (P< 0.05) associated with oseltamivir and oseltamivir carboxylate apparent clearance, but the correlation coefficient was poor (R2≤ 0.3). Creatinine clearance estimated by the Cockcroft-Gault method and lean body weight were also significantly (P< 0.05) but poorly (R2= 0.17) correlated with oseltamivir carboxylate apparent clearance. Since the systemic exposure of oseltamivir carboxylate is not reduced in class III obese adults with standard doses, a dose increment of oseltamivir is likely to be unnecessary.

scholarly journals Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System

2009 ◽  
Vol 53 (11) ◽  
pp. 4753-4761 ◽  
Author(s):  
Gerhard Hoffmann ◽  
Christoph Funk ◽  
Stephen Fowler ◽  
Michael B. Otteneder ◽  
Alexander Breidenbach ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Active Transport ◽  
Active Metabolite ◽  
Influenza A ◽  
Transport Processes ◽  
Oseltamivir Carboxylate ◽  
The Central Nervous System ◽  
Oral Doses

ABSTRACT Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.

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 Clinical Pharmacokinetics of Oseltamivir and Its Active Metabolite Oseltamivir Carboxylate after Oral Administration in Horses

2007 ◽  
Vol 69 (3) ◽  
pp. 293-296 ◽  
Author(s):  
Takashi YAMANAKA ◽  
Masayuki YAMADA ◽  
Koji TSUJIMURA ◽  
Takashi KONDO ◽  
Shunichi NAGATA ◽  
...  
Keyword(s):  
Oral Administration ◽  
Active Metabolite ◽  
Oseltamivir Carboxylate ◽  
Clinical Pharmacokinetics
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