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.
Highlights
Shikimic acid (3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid) was initially extracted from Illicium species, including I. anisatum and I. verum [1,2]
Shikimic acid is a critical starting material for semi-total synthesis of oseltamivir, which is used to treat and prevent influenza caused by the A and B viruses [1]
The absorption of shikimic acid has only been studied via in situ perfusion in rats [7], while the metabolism was explored over 40 years ago [8,9]
Summary
Shikimic acid (3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid) was initially extracted from Illicium species, including I. anisatum and I. verum [1,2]. The absorption of shikimic acid has only been studied via in situ perfusion in rats [7], while the metabolism was explored over 40 years ago [8,9]. Adamson et al reported that shikimic acid was converted into hippuric acid (via benzoate) after aromatization by the gut microflora of rats and monkeys [8]. This was disputed by Brewster et al several years later, who showed that shikimate was biotransformed by the gastrointestinal microflora into cyclohexanecarboxylate, which was aromatized and conjugated with glycine in mammalian tissues [9]
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