Abstract
Verproside, an active iridoid glycoside component of Veronica species, such as Pseudolysimachion rotundum var. subintegrum and Veronica anagallis-aquatica, possesses anti-asthma, anti-inflammatory, anti-nociceptive, antioxidant, and cytostatic activities. Verproside is metabolized into nine metabolites in human hepatocytes: verproside glucuronides (M1, M2) via glucuronidation, verproside sulfate (M3) via sulfation, picroside II (M4) and isovanilloylcatalpol (M5) via O-methylation, M4 glucuronide (M6) and M4 sulfate (M8) via further glucuronidation and sulfation of M4, and M5 glucuronide (M7) and M5 sulfate (M9) via further glucuronidation and sulfation of M5. Drug-metabolizing enzymes responsible for verproside metabolism, including sulfotransferase (SULT) and UDP-glucuronosyltransferase (UGT), were characterized. The formation of verproside glucuronides (M1, M2), isovanilloylcatalpol glucuronide (M7), and picroside II glucuronide (M6) was catalyzed by commonly expressed UGT1A1 and UGT1A9 and gastrointestinal-specific UGT1A7, UGT1A8, and UGT1A10, consistent with the higher intrinsic clearance values for the formation of M1, M2, M6, and M7 in human intestinal microsomes compared with those in liver microsomes. The formation of verproside sulfate (M3) and M5 sulfate (M9) from verproside and isovanilloylcatalpol (M5), respectively, was catalyzed by SULT1A1. Metabolism of picroside II (M4) into M4 sulfate (M8) was catalyzed by SULT1A1, SULT1E1, SULT1A2, SULT1A3, and SULT1C4. Based on these results, the pharmacokinetics of verproside may be affected by the co-administration of relevant UGT and SULT inhibitors or inducers.
Highlights
Verproside is a biologically active iridoid glycoside component of Pseudolysimachion rotundum var. subintegrum, Pseudolysimachionspurium, Pseudolysimachion longifolium, Veronica anagallis-aquatica, and Veronica ciliata [1,2,3,4]
liquid chromatography–high resolution quadrupole Orbitrap mass spectrometry (LC-HRMS) analysis of the extracts after a 2-h incubation of verproside with human hepatocytes resulted in nine metabolites (M1–M9), along with unchanged verproside (Figure 1)
M6 and M8 were identified after incubation of picroside II (M4) with human liver S9 fractions in the presence of uridine 50 -diphosphoglucuronic acid (UDPGA) and 3-phosphoadenosine- 5-phosphosulfate (PAPS)
Summary
Verproside is a biologically active iridoid glycoside component of Pseudolysimachion rotundum var. subintegrum, Pseudolysimachionspurium, Pseudolysimachion longifolium, Veronica anagallis-aquatica, and Veronica ciliata [1,2,3,4]. Verproside is a biologically active iridoid glycoside component of Pseudolysimachion rotundum var. Verproside exhibits anti-inflammatory [5,6,7], antioxidant [8], anti-nociceptive [6], anti-hepatocarcinoma [9], and anti-asthmatic activities. Molecules 2017, 22, 670 the pharmacokinetics and metabolism of verproside in rats [12,13], but the mechanisms underlying the in vitro and in vivo metabolism of verproside in animals and humans have not been reported. Sprague Dawley rats, indicating the extensive metabolism of verproside [12]. Verproside is metabolized into verproside glucuronides (M1, M2), verproside sulfates (M3, 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, M14), 3-methyoxy-4-hydroxybenzoic acid (M15), M15 glucuronides (M17, M18), M15 sulfate (M20), 3-hydroxy-4-methoxybenzoic acid (M16), M16 glucuronide (M19), and M16 sulfate (M21) via
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