Pharmacokinetics of Shikimic Acid Following Intragastric and Intravenous Administrations in Rats

Abstract

Shikimic acid, a critical starting material for the semi-total synthesis of oseltamivir to treat and prevent influenza, exerts many pharmacological effects. However, the optimal bioanalytical method has not been adequately defined. We used liquid chromatography-tandem mass spectrometry to quantitate shikimic acid in rat plasma and studied its pharmacokinetics after intragastric and intravenous administration. Plasma was spiked with an internal standard, and the proteins were precipitated with acetonitrile, followed by solvent evaporation and reconstitution of the mobile phase. Shikimic acid was separated on a hydrophilic reverse-phase column and showed a mass transition ([M-H]−) at m/z 173.4→136.6. Shikimic acid exhibited bi-exponential decay after intravenous dosing, with a rapid distribution (5.57 h−1) up to 1 h followed by slow elimination (0.78 h−1). The steady state distribution and clearance volumes were 5.17 and 1.79 L/h/kg, respectively. After intragastric administration, the shikimic acid level peaked at about 3 h, and the material then disappeared mono-exponentially with a half-life of 1.3 h. A double peak phenomenon was observed. The absolute oral bioavailability was about 10% in rats. We explored the relationship between the pharmacokinetics and pharmacodynamics of shikimic acid.

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“…We attempted to quantify shikimic acid levels in serum samples by adapting a published HPLC-SRM-MS–based method ( Noh et al. 2020 ).…”

“…The experimental protocol used to quantify shikimic acid in serum was based on a published method (Noh et al 2020). Shikimic acid was quantified by HPLC-MS/MS with a Thermo Scientific Quantum Access mass spectrometer with a Thermo Accela LC pump and CTC autosampler.…”

“…We attempted to quantify shikimic acid levels in serum samples by adapting a published HPLC-SRM-MS-based method (Noh et al 2020). A comparison of serum and water samples spiked with shikimic acid with a mixture of shikimic acid and albumin revealed that the presence of protein in serum severely compromised the recovery and sensitivity of detection of this compound (Figures S3 and S4).…”