Metabolism and Pharmacokinetics of Mangiferin in Conventional Rats, Pseudo-Germ-Free Rats, and Streptozotocin-Induced Diabetic Rats

Abstract

ABSTRACT:To clarify the role of the intestinal flora in the absorption and metabolism of mangiferin and to elucidate its metabolic fate and pharmacokinetic profile in diabetic rats, a systematic and comparative investigation of the metabolism and pharmacokinetics of mangiferin in conventional rats, pseudo-germ-free rats, and streptozotocin (STZ)-induced diabetic rats was conducted. Forty-eight metabolites of mangiferin were detected and identified in the urine, plasma, and feces after oral administration (400 mg/kg). Mangiferin underwent extensive metabolism in conventional rats and diabetic rats, but the diabetic rats exhibited a greater number of metabolites compared with that of conventional rats. When the intestinal flora were inhibited, deglycosylation of mangiferin and sequential biotransformations would not occur. Pharmacokinetic studies indicated a 2.79-and 2.35-fold increase in the plasma maximum concentration and the area under the concentration-time curve from 0 to 24 h of mangiferin in diabetic rats compared with those for conventional rats, whereas no significant differences were observed between conventional rats and pseudo-germ-free rats. Further real-time quantitative reverse transcription-polymerase chain reaction results indicated that the multidrug resistance (mdr) 1a level in the ileum increased, whereas its level in the duodenum and the mdr1b mRNA levels in the duodenum, jejunum, and ileum decreased in diabetic rats compared with those in conventional rats. With regard to the pseudo-germ-free rats, up-regulated mdr1a mRNA levels and down-regulated mdr1b mRNA levels in the small intestines were observed. The diabetic status induced increased UDP-glucuronosyltransferase (UGT) 1A3, UGT1A8, UGT2B8, and sulfotransferase (SULT) 1A1 mRNA levels and decreased catechol-Omethyltransferase (COMT), UGT2B6, UGT2B12, and SULT1C1 mRNA levels. These results might partially explain the different pharmacokinetic and metabolic disposition of mangiferin among conventional and model rats.

Comparative Pharmacokinetic Study of Mangiferin in Normal and Alloxan-Induced Diabetic Rats after Oral and Intravenous Administration by UPLC-MS/MS

“…It is well known that DM induces morphological and/or functional complications that affect eyes, kidneys, gastrointestinal tract, peripheral, and autonomic nervous systems in DM patients [9][10][11] and DM animals [12][13][14][15][16]. Hence, these complications indicate that DM may alter the pharmacokinetic profiles of mangiferin.…”

“…Hence, these complications indicate that DM may alter the pharmacokinetic profiles of mangiferin. Liu et al [13] demonstrated a 2.79-and 2.35-fold increase in the plasma maximum concentration (C max ) and the area under the concentration-time curve from 0 to 24 h (AUC 0-24h ) of mangiferin in streptozotocin (STZ)-induced diabetic rats compared with those in conventional rats.…”

Defining the Role of Gut Bacteria in the Metabolism of Deleobuvir: In Vitro and In Vivo Studies

“…Similarly, species differences in gut microbiota (Rowland et al, 1986) make interspecies extrapolations difficult. Germ-free rats have been used to evaluate the role of bacterial microbiota in the metabolism of several compounds, including hesperidin, acetaminophen, and mangiferin (Jin et al, 2010;Lee et al, 2012;Liu et al, 2012). There are significant challenges in the maintenance and use of germ-free animals (Gordon and Pesti, 1971).…”

“…However, the limitations of large interspecies differences in microbiota composition and distribution have to be taken into consideration (Rowland et al, 1986;Sousa et al, 2008). Pseudo-germ free (pGF) rats can be created by treatment with broadspectrum antibiotics and have helped in elucidating the role of gut bacteria in the metabolism of drugs (Jin et al, 2010;Lee et al, 2012;Liu et al, 2012;Yoo et al, 2014).…”

The Pharmacokinetics and Metabolism of Neomangiferin, a Major Bioactive Component in Anemarrhena asphodeloides

“…The metabolism and pharmacokinetic profiles of mangiferin have recently been examined [16][17][18]. Pharmacokinetic studies have indicated that mangiferin exhibits poor oral bioavailability (1.2%) when orally administered with the isolated compound directly [19].…”