Abstract
Verproside, a catalpol derivative iridoid glycoside isolated from Pseudolysimachion rotundum var. subintegrum, is a biologically active compound with anti-inflammatory, antinociceptic, antioxidant, and anti-asthmatic properties. Twenty-one metabolites were identified in bile and urine samples obtained after intravenous administration of verproside in rats using liquid chromatography-quadrupole Orbitrap mass spectrometry. Verproside was metabolized by O-methylation, glucuronidation, sulfation, and hydrolysis to verproside glucuronides (M1 and M2), verproside sulfates (M3 and M4), picroside II (M5), M5 glucuronide (M7), M5 sulfate (M9), isovanilloylcatalpol (M6), M6 glucuronide (M8), M6 sulfate (M10), 3,4-dihydroxybenzoic acid (M11), M11 glucuronide (M12), M11 sulfates (M13 and M14), 3-methyoxy-4-hydroxybenzoic acid (M15), M15 glucuronides (M17 and M18), M15 sulfate (M20), 3-hydroxy-4-methoxybenzoic acid (M16), M16 glucuronide (M19), and M16 sulfate (M21). Incubation of verproside with rat hepatocytes resulted in thirteen metabolites (M1–M11, M13, and M14). Verproside sulfate, M4 was a major metabolite in rat hepatocytes. After intravenous administration of verproside, the drug was recovered in bile (0.77% of dose) and urine (4.48% of dose), and O-methylation of verproside to picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation was identified as major metabolic pathways compared to glucuronidation and sulfation of verproside in rats.
Highlights
IntroductionVerproside, a catalpol derivative iridoid glycoside isolated from Pseudolysimachion spurium, Pseudolysimachion rotundum var. subintegrum, Pseudolysimachion longifolium and Veronica anagallis-aquatica etc., shows potent anti-inflammatory, antioxidant, and antinociceptic activities [1,2,3,4,5]
In this work the in vivo metabolites of verproside in the bile and urine samples obtained after intravenous administration of verproside, and the predominant metabolites formed from in vitro incubation of verproside and its possible metabolites from rat liver S9 fractions and hepatocytes were elucidated using liquid chromatography-high resolution quadrupole Orbitrap mass spectrometry (LC-HRMS)
LC-HRMS analysis of the bile and urine samples obtained after intravenous injection of verproside to rats resulted in twenty-one metabolites (M1–M21), along with unchanged verproside (Figures 1 and 2)
Summary
Verproside, a catalpol derivative iridoid glycoside isolated from Pseudolysimachion spurium, Pseudolysimachion rotundum var. subintegrum, Pseudolysimachion longifolium and Veronica anagallis-aquatica etc., shows potent anti-inflammatory, antioxidant, and antinociceptic activities [1,2,3,4,5]. The pharmacokinetics of verproside were evaluated in rats after intravenous (dose range 2–10 mg/kg) and oral (dose range 20–100 mg/kg) administration [7,8]. 0.5%) in male Sprague-Dawley rats suggest that verproside may be extensively metabolized [8]. Isovanilloylcatalpol was identified as a metabolite of verproside after intravenous administration, but was not detected after oral administration to rats in our previous study [8]. It is necessary to elucidate the other metabolic pathways of verproside in rats, aside from the formation of isovanilloylcatalpol, for characterization of its pharmacodynamics and toxicity. In this work the in vivo metabolites of verproside in the bile and urine samples obtained after intravenous administration of verproside, and the predominant metabolites formed from in vitro incubation of verproside and its possible metabolites from rat liver S9 fractions and hepatocytes were elucidated using liquid chromatography-high resolution quadrupole Orbitrap mass spectrometry (LC-HRMS)
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