Metabolism and disposition of oseltamivir (OS) in rats, determined by immunohistochemistry with monospecific antibody for OS or its active metabolite oseltamivir carboxylate (OC): A possibility of transporters dividing the drugs’ excretion into the bile and kidney

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.

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01541-08 ◽

2009 ◽

Vol 53 (11) ◽

pp. 4753-4761 ◽

Cited By ~ 22

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.

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

Journal of Veterinary Medical Science ◽

10.1292/jvms.69.293 ◽

2007 ◽

Vol 69 (3) ◽

pp. 293-296 ◽

Cited By ~ 4

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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Simple and sensitive assay for quantification of oseltamivir and its active metabolite oseltamivir carboxylate in human plasma using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry: Improved applicability to pharmacokinetic study

Journal of Pharmaceutical and Biomedical Analysis ◽

10.1016/j.jpba.2012.08.029 ◽

2013 ◽

Vol 72 ◽

pp. 245-250 ◽

Cited By ~ 14

Author(s):

Zhe-Yi Hu ◽

S. Casey Laizure ◽

Bernd Meibohm ◽

Vanessa L. Herring ◽

Robert B. Parker

Keyword(s):

Mass Spectrometry ◽

High Performance Liquid Chromatography ◽

Liquid Chromatography ◽

Tandem Mass Spectrometry ◽

Active Metabolite ◽

High Performance ◽

Tandem Mass ◽

Sensitive Assay ◽

Oseltamivir Carboxylate ◽

Ionization Tandem Mass Spectrometry

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Pharmacokinetics of Orally Administered Oseltamivir in Healthy Obese and Nonobese Thai Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01786-13 ◽

2013 ◽

Vol 58 (3) ◽

pp. 1615-1621 ◽

Cited By ~ 13

Author(s):

Podjanee Jittamala ◽

Sasithon Pukrittayakamee ◽

Joel Tarning ◽

Niklas Lindegardh ◽

Warunee Hanpithakpong ◽

...

Keyword(s):

Active Metabolite ◽

Severe Disease ◽

Influenza Viruses ◽

Pharmacokinetic Parameters ◽

Oseltamivir Carboxylate ◽

Significant Difference ◽

Pharmacokinetic Properties ◽

2009 H1n1 ◽

Obese Subjects ◽

Body Mass Indexes

ABSTRACTOseltamivir is the most widely used anti-influenza drug. In the 2009 H1N1 pandemic, in which the influenza viruses were oseltamivir sensitive, obesity was identified as a risk factor for severe disease and unfavorable outcomes. The aim of this study was to investigate the pharmacokinetic properties of oseltamivir and its active metabolite, oseltamivir carboxylate, in obese and nonobese healthy subjects. A single-dose, randomized, two-sequence crossover study was conducted in 12 obese and 12 nonobese healthy Thai volunteers. Each volunteer was given 75 mg and 150 mg oseltamivir orally with an intervening washout period of more than 3 days. The pharmacokinetic properties of oseltamivir and oseltamivir carboxylate were evaluated using a noncompartmental approach. The median (range) body mass indexes (BMIs) for obese subjects were 33.8 kg/m2(30.8 to 43.2) and 22.2 (18.8 to 24.2) for nonobese subjects. The pharmacokinetic parameters of oseltamivir carboxylate, the active metabolite of oseltamivir, were not significantly different between obese and nonobese subjects for both 75-mg and 150-mg doses. Both doses were well tolerated. Despite the lower dose per kilogram body weight in obese subjects, there was no significant difference in the exposure of oseltamivir carboxylate between the obese and nonobese groups. Standard dosing is appropriate for obese subjects. (The study was registered at ClinicalTrials.gov under registration no. NCT 01049763.)

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

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/2008/927574 ◽

2008 ◽

Vol 2008 ◽

pp. 1-5 ◽

Cited By ~ 29

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.

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