Dose-Independent ADME Properties and Tentative Identification of Metabolites of α-Mangostin from Garcinia mangostana in Mice by Automated Microsampling and UPLC-MS/MS Methods

Abstract

The information about a marker compound's pharmacokinetics in herbal products including the characteristics of absorption, distribution, metabolism, excretion (ADME) is closely related to the efficacy/toxicity. Also dose range and administration route are critical factors to determine the ADME profiles. Since the supply of a sufficient amount of a marker compound in in vivo study is still difficult, pharmacokinetic investigations which overcome the limit of blood collection in mice are desirable. Thus, we have attempted to investigate concurrently the ADME and proposed metabolite identification of α-mangostin, a major constituent of mangosteen, Garcinia mangostana L, in mice with a wide dose range using an in vitro as well as in vivo automated micro-sampling system together. α-mangostin showed dose-proportional pharmacokinetics at intravenous doses of 5–20 mg/kg and oral doses of 10–100 mg/kg. The gastrointestinal absorption of α-mangostin was poor and the distribution of α-mangostin was relatively high in the liver, intestine, kidney, fat, and lung. α-mangostin was extensively metabolized in the liver and intestine. With regards to the formation of metabolites, the glucuronidated, bis-glucuronidated, dehydrogenated, hydrogenated, oxidized, and methylated α-mangostins were tentatively identified. We suggest that these dose-independent pharmacokinetic characteristics of α-mangostin in mice provide an important basis for preclinical applications of α-mangostin as well as mangosteen. In addition, these experimental methods can be applied to evaluate the pharmacokinetics of natural products in mice.

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“…Subsequently, α-MG was detected to be transported into various cell lines (macrophage-like THP-1, hepatic HepG2, enterocyte-like Caco-2, and colon HT-29), where it underwent phase II metabolism and biotransformation to get converted into other xanthones [126]. By in vitro metabolism studies using tissue homogenates, α-MG was proven to be metabolized mainly via the liver and small intestine [127,128]. With regards to the formation of metabolites, the glucuronidated, bis-glucuronidated, dehydrogenated, hydrogenated, oxidized, and methylated α-MG were tentatively identified [128].…”

“…By in vitro metabolism studies using tissue homogenates, α-MG was proven to be metabolized mainly via the liver and small intestine [127,128]. With regards to the formation of metabolites, the glucuronidated, bis-glucuronidated, dehydrogenated, hydrogenated, oxidized, and methylated α-MG were tentatively identified [128]. In vivo animal studies showed that the majority of α-MG occurred in the plasma as phase II metabolites and only minimal amounts as free forms after oral administration [129].…”

“…Phase II metabolites displayed a prolonged half-life compared to the free compound because they underwent enterohepatic recirculation and were reabsorbed from the bile to the intestine and back into the bloodstream again [129]. Recently, α-MG was reported to have dose-independent (linear) pharmacokinetics at oral doses of 10-100 mg/kg BW in mice [128]. After oral administration, α-MG (10 mg/kg) was detected in the plasma at the point of 5 min, indicating a rapid gastrointestinal absorption, and was then assigned to most tissues except the brain; it was relatively high in the liver, intestine, kidney, fat, and lung [127,128].…”

“…Recently, α-MG was reported to have dose-independent (linear) pharmacokinetics at oral doses of 10-100 mg/kg BW in mice [128]. After oral administration, α-MG (10 mg/kg) was detected in the plasma at the point of 5 min, indicating a rapid gastrointestinal absorption, and was then assigned to most tissues except the brain; it was relatively high in the liver, intestine, kidney, fat, and lung [127,128].…”

“…The oral bioavailability of α-MG, however, is very low, only 2.29 % of oral α-MG at 10 mg/kg in mice [128], which is likely due to its intensive first-pass metabolism [127,135] as well as poor absorption caused by low water solubility and the efflux effect of P-gp [136]. The low oral bioavailability has limited its further pharmacological exploitation.…”