Development of a high-performance liquid chromatographic–mass spectrometric assay for the specific and sensitive quantification of Ro 64-0802, an anti-influenza drug, and its pro-drug, oseltamivir, in human and animal plasma and urine

Wiltshire, Hugh; Wiltshire, B.; Citron, Andrea; Clarke, Tony; Serpe, Carolyn; Gray, D. Anthony; Herron, William J.

doi:10.1016/s0378-4347(00)00300-5

Cited by 92 publications

(92 citation statements)

References 6 publications

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“…Plasma levels of oseltamivir free base and its active metabolite carboxylate were measured by means of high-performance liquid chromatography with tandem mass spectrometry, as previously described. 6 The lower limit of detection was 1.0 μg/L for oseltamivir free base and 10 μg/L for the carboxylate metabolite.…”

Section: Pharmacokinetic Analysismentioning

confidence: 93%

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

Ariano¹,

Sitar²,

Zelenitsky³

et al. 2010

Canadian Medical Association Journal

105

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Section: Pharmacokinetic Analysismentioning

confidence: 93%

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

Ariano¹,

Sitar²,

Zelenitsky³

et al. 2010

Canadian Medical Association Journal

105

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“…As it has been reported that rat intestinal PEPT1 expression shows a diurnal rhythm, all the in vivo studies were conducted at the same time of the day (Pan et al, 2004). Quantification of oseltamivir and Ro 64-0802 in plasma and brain tissues was performed using reported methods (Wiltshire et al, 2000) with some modification. In brief, aliquots of brain tissues (100 mg) were homogenized with 1 ml of 5 mM ammonium acetate buffer, followed by centrifugation at 1700g, and 0.9 ml of the supernatant was subjected to solid-phase extraction (Empore Mixed Phase Cation, 7 mm/3 ml; 3M Bioanalytical Technologies, St. Paul, MN).…”

Section: Oseltamivir Is a Substrate Of Pept1mentioning

confidence: 99%

Oseltamivir (Tamiflu) Is a Substrate of Peptide Transporter 1

Ogihara¹,

Kano²,

Wagatsuma³

et al. 2009

Drug Metab Dispos

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ABSTRACT:Oseltamivir, an ester-type prodrug of the neuraminidase inhibitor [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), has been developed for the treatment of A and B strains of the influenza virus but has neuropsychiatric and other side effects. In this study, we characterized the transport across intestinal epithelial cells and the absorption of oseltamivir in rats. Uptake by Caco-2 cells (human carcinoma cell line) and HeLa cells transfected with peptide transporter 1 (HeLa/ PEPT1) was time-and temperature-dependent and was inhibited by typical PEPT1 inhibitors such as glycyl-sarcosine (Gly-Sar). The uptake by Caco-2 cells and HeLa/PEPT1 was saturable, with similar K m values. Oseltamivir absorption in adult rats was greatly reduced by simultaneous administration of milk, casein, or Gly-Sar. Furthermore, the plasma and brain concentrations of oseltamivir were higher in fasting than in nonfasting rats after oral administration. These results suggest that oseltamivir is a substrate of PEPT1 and that PEPT1 is involved in its intestinal absorption.Various transporters are expressed on apical and basolateral membranes of intestinal epithelial cells, serving to take up nutrients and to excrete xenobiotics into the lumen. Influx transporters are able to accept nutrients and also various drugs as substrates. In particular, peptide transporter 1 (PEPT1, SLC15A1), localized at brush-border membranes of human small intestine (Saito et al., 1995), plays important roles in the absorption of not only di-/tripeptides (Tamai et al., 1994) but also peptide-mimetic compounds, such as orally administered ␤-lactam antibiotics (Ganapathy et al., 1995;Sai et al., 1996) and the anticancer agent bestatin (Tomita et al., 1990;Inui et al., 1992). Several researchers recently found that intestinal PEPT1 can transport L-valine ester prodrugs, such as valacyclovir and valganciclovir (Balimane et al., 1998;Han et al., 1998;Sugawara et al., 2000). Therefore, such structural modification of drugs may result in increased intestinal absorption, mediated by PEPT1.Oseltamivir phosphate (oseltamivir), manufactured under the trade name Tamiflu as an ester-type prodrug of the neuraminidase inhibitor Ro 64-0802, has been developed for the treatment of A and B strains of the influenza virus. This drug has been reported to be associated with neuropsychiatric side effects (http://www.fda.gov/cder/drug/ infopage/tamiflu/QA20051117.htm and http://www.mhlw.go.jp/ english/index.html), which are likely to be caused by distribution of oseltamivir and/or its metabolite(s) to the central nervous system. We recently examined the possible role of P-glycoprotein (P-gp) as the determinant of brain distribution of oseltamivir and Ro 64-0802 both in vitro using LLC-GA5-COL150 cells, which overexpress human multidrug resistance (or resistant) 1 (MDR1) P-gp on the apical membrane, and in vivo using mdr1a/1b knockout mice (Morimoto et al., 2008). The permeability of oseltamivir in the basolateral-to-apical dire...

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“…Literature survey for oseltamivir analysis revealed several methods based on different techniques, viz. LC-MS assay for it's quantification in plasma and urine, 5) LC assay for evaluation of Tamiflu 6) and HPLC method for the determination of oseltamivir in Tamiflu. 7)…”

mentioning

confidence: 99%

Stability Indicating RP-HPLC Method Development and Validation for Oseltamivir API

Narasimhan

Abida

Srinivas

2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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Oseltamivir is an antiviral drug used in the treatment and prophylaxis of influenza virus A and B infections. It was developed by Gilead Sciences and is currently marketed by Haffmann-La Roche (Roche) under the trade name Tamiflu. Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate. It is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. Oseltamivir carboxylate is eliminated entirely by renal excretion. Less than 20% of an oral radiolabeled dose is eliminated in feces.1) Chemically it is (3R,4R,5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester. 2)Stability testing forms an important part of the process of drug product development. The purpose of stability testing is to provide evidence on how the quality of a drug substance varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommendation of storage conditions, retest periods, and shelf life to be established. The assay of oseltamivir API (Active Pharmaceutical Ingredient) in stability test sample needs to be determined using stability indicating method, as recommended by the International Conference on Harmonization (ICH) guidelines 3) and USP.4)The present work was designed to develop a simple, precise and rapid analytical LC procedure, which would serve as stability indicating assay method for analysis of oseltamivir API. Literature survey for oseltamivir analysis revealed several methods based on different techniques, viz. LC-MS assay for it's quantification in plasma and urine, 5) LC assay for evaluation of Tamiflu 6) and HPLC method for the determination of oseltamivir in Tamiflu. 7)The present study is the first time report on stability indicating assay of oseltamivir in presence of degradation products by HPLC. In this method gradient elution method is selected for the analysis of oseltamivir API because it gave better base line separation and peak width, which is suitable for the routine analysis of oseltamivir. Although the gradient elution method uses two-pump system, the gradient run provided a proper peak with baseline, which prompted us to select this method for the analysis of oseltamivir API.In view of above in the present study we hereby report the development and validation of a stability indicating gradient reverse-phase HPLC (RP-HPLC) method for analysis of oseltamivir API in presence of degradation products as per ICH guidelines.In order to establish the stability indicating nature of the method, force degradation of oseltamivir was performed under various stress conditions (basic, acidic and oxidative), and stressed samples were analyzed by the proposed method. The proposed LC method was able to separate the drug from degradation products generated during forced degradation studies. The developed method was validated as per ICH guidelines 8) and its updated international convention.9) The linearity of response, preci...

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Development of a high-performance liquid chromatographic–mass spectrometric assay for the specific and sensitive quantification of Ro 64-0802, an anti-influenza drug, and its pro-drug, oseltamivir, in human and animal plasma and urine

Cited by 92 publications

References 6 publications

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza

Oseltamivir (Tamiflu) Is a Substrate of Peptide Transporter 1

Stability Indicating RP-HPLC Method Development and Validation for Oseltamivir API

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