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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.

Han SY, You BH, Kim YC, Chin YW, Choi YH - PLoS ONE (2015)

Bottom Line: Also dose range and administration route are critical factors to determine the ADME profiles.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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy and BK21 PLUS R-FIND Team, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do, 410-820, South Korea.

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.

No MeSH data available.


Related in: MedlinePlus

Proposed structures and metabolic pathways of metabolites in mice’s plasma, urine, feces, liver and small intestine after intravenous and oral administration of α-MG and S9 fractions of the liver and small intestine after 30 min incubation.
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pone.0131587.g007: Proposed structures and metabolic pathways of metabolites in mice’s plasma, urine, feces, liver and small intestine after intravenous and oral administration of α-MG and S9 fractions of the liver and small intestine after 30 min incubation.

Mentions: In aspect of extensive metabolism of α-MG, the chemical structures of the metabolites from α-MG were elucidated by LC-MS and MS/MS modes providing the [M+H]+ of α-MG, parent compounds and daughter ions thus giving more structural information. The components that presented at high concentrations were assumed to be the parent compounds [41] and the tentative metabolic pathways of α-MG were as follows: glucuronide conjugation (m/z 587.3 → 531.1 or 355.1), bis-glucuronide conjugation (m/z 763.3 → 707.1 or 355.1), dehydrogenation (m/z 409.2 → 353.0), hydrogenation (m/z 413.3 → 357.1), oxidation (m/z 427.2 → 371.1 or 355.1), and methylation (m/z 425.3 → 369.1). The probable metabolites suggest that α-MG was metabolized via phase I/II reactions. The enzymatic reactions such as glucuronide and bis-glucuronide conjugation via UGTs and oxidation, methylation, hydrogenation and dehydrogenation via CYPs, respectively [42], [43], supported the metabolic pathways of α-MG shown in Fig 7 [44].


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.

Han SY, You BH, Kim YC, Chin YW, Choi YH - PLoS ONE (2015)

Proposed structures and metabolic pathways of metabolites in mice’s plasma, urine, feces, liver and small intestine after intravenous and oral administration of α-MG and S9 fractions of the liver and small intestine after 30 min incubation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4503439&req=5

pone.0131587.g007: Proposed structures and metabolic pathways of metabolites in mice’s plasma, urine, feces, liver and small intestine after intravenous and oral administration of α-MG and S9 fractions of the liver and small intestine after 30 min incubation.
Mentions: In aspect of extensive metabolism of α-MG, the chemical structures of the metabolites from α-MG were elucidated by LC-MS and MS/MS modes providing the [M+H]+ of α-MG, parent compounds and daughter ions thus giving more structural information. The components that presented at high concentrations were assumed to be the parent compounds [41] and the tentative metabolic pathways of α-MG were as follows: glucuronide conjugation (m/z 587.3 → 531.1 or 355.1), bis-glucuronide conjugation (m/z 763.3 → 707.1 or 355.1), dehydrogenation (m/z 409.2 → 353.0), hydrogenation (m/z 413.3 → 357.1), oxidation (m/z 427.2 → 371.1 or 355.1), and methylation (m/z 425.3 → 369.1). The probable metabolites suggest that α-MG was metabolized via phase I/II reactions. The enzymatic reactions such as glucuronide and bis-glucuronide conjugation via UGTs and oxidation, methylation, hydrogenation and dehydrogenation via CYPs, respectively [42], [43], supported the metabolic pathways of α-MG shown in Fig 7 [44].

Bottom Line: Also dose range and administration route are critical factors to determine the ADME profiles.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.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy and BK21 PLUS R-FIND Team, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do, 410-820, South Korea.

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.

No MeSH data available.


Related in: MedlinePlus