Abstract
Oseltamivir (OA), an ethyl ester prodrug of oseltamivir carboxylate (OC), is clinically used as a potent and selective inhibitor of neuraminidase. Chinese medicines have been advocated to combine with conventional drug for avian influenza. The current study aims to investigate the potential pharmacokinetic and pharmacodynamic interactions of a Chinese medicine formula, namely, Yin Qiao San and Sang Ju Yin (CMF1), commonly used for anti-influenza in combination with OA in both rat and human, and to reveal the underlined mechanisms. It was found that although C max, AUC and urinary recovery of OC, as well as metabolic ratio (AUCOC/AUCOA), were significantly decreased in a dose-dependent manner following combination use of CMF1 and OA in rat studies (P < 0.01), such coadministration in 14 healthy volunteers only resulted in a trend of minor decrease in the related parameters. Further mechanistic studies found that although CMF1 could reduce absorption and metabolism of OA, it appears to enhance viral inhibition of OA (P < 0.01). In summary, although there was potential interaction between OA and CMF1 found in rat studies, its clinical impact was expected to be minimal. The coadministration of OA and CMF1 at the clinical recommended dosages is, therefore, considered to be safe.
Highlights
Oseltamivir (OA) is clinically used as a potent and selective inhibitor of neuraminidase essential for replication of influenza A and B viruses
The present study aims to determine, in animal and human studies, the potential pharmacokinetic and pharmacodynamic interactions of OA in combination with the most recognized and thirteen herb containing Chinese medicine (CM) formulae (CMF1, Table 1), which is a combined formula of two traditional Chinese herb preparations, Yin Qiao San and Sang Ju Yin, for avian influenza as recommended by a CM expert panel from the HA in Hong Kong
The noncompartmental model was employed to estimate the pharmacokinetic parameters including time of maximum observed concentration (Tmax), concentration corresponding to Tmax (Cmax), terminal half-life (t1/2) and area under curve from time zero to the last sampling time (AUC0–t) for plasma samples, and the 12 h cumulative amount of analytes (Ae) excreted in urine
Summary
Oseltamivir (OA) is clinically used as a potent and selective inhibitor of neuraminidase essential for replication of influenza A and B viruses. Following 50 mg doses, the maximum plasma oseltamivir carboxylate concentration is about 230 μg/L, which is above of 50% inhibitory concentrations (IC50) of many influenza A viruses [1]. The pharmacokinetics of both OA and its active metabolite oseltamivir carboxylate (OC) have been studied in young healthy adults and children, as well as elderly subjects [1,2,3,4]. The present study aims to determine, in animal and human studies, the potential pharmacokinetic and pharmacodynamic interactions of OA in combination with the most recognized and thirteen herb containing CM formulae (CMF1, Table 1), which is a combined formula of two traditional Chinese herb preparations, Yin Qiao San and Sang Ju Yin, for avian influenza as recommended by a CM expert panel from the HA in Hong Kong
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