Abstract
In view of the limited information on the pharmacokinetics of oseltamivir (OSE) during pregnancy, this study aims to evaluate the placental transportation of OSE and its active metabolite oseltamivir carboxylic acid (OCA) in rats. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) system coupled to an in vivo transplacental model has been developed to determine OSE and OCA in the placenta, amniotic fluids and fetus of 13-day pregnant Sprague-Dawley rats. Concentrations of OSE and OCA in plasma, amniotic fluids, placenta, and fetus were measured by the validated LC-MS/MS after OSE administration (10 mg/kg, iv). The pharmacokinetic data of both analytes were examined by non-compartmental modeling. The area under the concentration-time curve (AUC) of OCA in maternal plasma was found to be 3.6 times larger than that of OSE. The AUCs of OCA in both amniotic fluid and fetus were significantly decreased, in comparison with that in maternal plasma (reduced by 76.7 and 98.1%, respectively). We found that both OSE and OCA can penetrate the placenta, amniotic fluids and fetus in rats during pregnancy; however, the penetration of OCA was much lower than that of OSE. The mother-to-fetus transfer ratio was defined as AUCfetus/AUCmother. The data demonstrated that the mother-to-fetus transfer ratio of OSE and OCA were 1.64 and 0.019, respectively, suggesting that OSE, but not OCA, penetrated through the placenta. Moreover, OCA might not be easily metabolized in the fetus due to the lack of carboxylase in the fetus.
Highlights
A new subtype of influenza A (H1N1) virus resulted in the outbreak of an influenza pandemic, referred to as pandemic H1N1, in 2009
Method validation OSE, oseltamivir carboxylic acid (OCA) and the internal standard were detected in the positive Multiple reaction monitoring (MRM) mode and their retention times were approximately 2.5, 6.6 and 1.6 min, respectively
The assays of recovery and matrix effect were used both to assess the influence of the biological matrix on the mass signals of analytes and to estimate the amount of each analyte collected after sample preparation
Summary
A new subtype of influenza A (H1N1) virus resulted in the outbreak of an influenza pandemic, referred to as pandemic H1N1, in 2009. High-risk populations include very young children, the elderly and pregnant women. Of these high-risk populations, pregnant women must be especially cautious because of the high risk of influenza-related complications in their unborn babies [1]. The OSE phosphate (TamifluH) is an antiviral drug and an ethyl ester prodrug of the active neuraminidase inhibitor, OCA. It is rapidly hydrolyzed by a liver enzyme, carboxylesterase, to become the active metabolite, OCA. OSE is usually administered orally for the treatment and prophylaxis of influenza virus infection [3]
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