Elucidation of Arctigenin Pharmacokinetics After Intravenous and Oral Administrations in Rats: Integration of In Vitro and In Vivo Findings via Semi-mechanistic Pharmacokinetic Modeling

Abstract

Abstract. Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max , K m , and Cl int of 47.5±3.4 nmol/min/mg, 204±22 μM, and 233±9 μl/min/ mg with intestinal microsomes and 2.92±0.07 nmol/min/mg, 22.7±1.2 μM, and 129±4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4′-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r 2 >0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses.

Gender-Dependent Pharmacokinetics of Veratramine in Rats: In Vivo and In Vitro Evidence

“…However, due to the much higher oral dose, the uptake of veratramine-3-O-sulfate into bile canaliculi may be slower than the formation of veratramine-3-O-sulfate in the hepatocytes, thus, veratramine-3-O-sulfate was found in plasma and urine in addition to bile. Such explanation for the potential routedependent disproportionate increase of parent compounds and metabolites across doses due to saturation of biliary excretion was also found in previous studies (74,75). Moreover, although the gender differences on the malepredominant urinary accumulation of 7-hydroxyl-veratramine and female-predominant biliary excretion of veratramine-3-O-sulfate were distinct after both oral and i.v.…”

Identification and characterization of human UDP-glucuronosyltransferases responsible for the in-vitro glucuronidation of arctigenin

“…The formation of AR‐4′‐O‐glucuronidation could also be observed in HIM, which is consistent with previous report that AR could be transformed to its 4′‐O‐glucuronide in rat intestine microsomes [21]. The kinetic analysis demonstrated that human intestine played an important role in AR‐4′‐O‐glucuronidation with Cl int value of 776 μl/min/mg protein in HIM, implying that AR may undergo a first‐pass metabolism during the absorption process.…”

“…This could be partially explained by the fact that rat UGT1A9 is a pseudogene and the propofol O‐glucuronidation activity in rat liver is much lower than that in human liver [22,23]. These findings agreed well with the observation of rapid formation of 4′‐O‐glucuronide after both oral and IV administration of AR,[21] indicating that AR may be rapidly eliminated from human body via glucuronidation pathway.…”

“…It is also worthy to mention that the corresponding Cl int of AR in RLM was 129 μl/min/mg according to a previous report,[21] which is much lower than that in HLM as demonstrated in this study. This could be partially explained by the fact that rat UGT1A9 is a pseudogene and the propofol O‐glucuronidation activity in rat liver is much lower than that in human liver [22,23].…”

Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

“…It is reported that AG can be metabolized to be arctigenic acid and arctigenin-4′- O -glucuronide in rats’ plasma by oral administration (Gao et al, 2014a). And there were different tissue distribution in SD rats (He et al, 2013).…”