Conjugated metabolites represent the major circulating forms ofAbelmoschus manihot in vivoand show an altered pharmacokinetic profile in renal pathology

Abstract

Objective: Flavonoids are main active components of A. manihot, which can be transformed into glucuronide/sulfate conjugates in vivo. Exploring the pharmacokinetic profile of these conjugates is necessary to further elucidate the mechanism of action. Material and method: Flavonoid fraction of A. manihot (FFA) was extracted from A. manihot flower with ethanol. FFA (400 mg/kg) was orally given to normal rats and chronic kidney disease (CKD) model rats. Blood samples were collected at 5, 15, 30, 45, 60, 90, 120, 240, 360, and 720 min after administration. The plasma concentrations of quercetin and isorhamnetin glucuronide/sulfate conjugates were analyzed by UPLC-MS/MS. Results: In normal rats, AUC of quercetin-glucuronide conjugates, isorhamnetin-glucuronide conjugates, quercetin-sulfate conjugates, and isorhamnetin-sulfate conjugates was 459. 45 ± 192.70, 1153.01 ± 697.04, 417.81 ± 220.31, and 2475.19 ± 1085.22 mmol h/L, respectively. While AUC of quercetin and isorhamnetin was 5.47 ± 2.54 and 30.73 ± 25.95 mmol h/L. AUC of the glucuronide-sulfate conjugates of quercetin and isorhamnetin is 125-times higher than that of aglycone (quercetin and isorhamnetin), showing that glucuronide/sulfate conjugates represent the major circulating forms of A. manihot flavonoid in vivo. AUC of isorhamnetinglucuronide conjugates and quercetin-sulfate conjugates was 719.65 ± 619.22 and 275.49 ± 1 60.95 mmol h/L, indicating that less conjugated metabolites were formed in CKD rats compared with normal rats. The ratio of AUC glucuronide/sulfate /AUC aglycone decreased from 125 to 104, which implied the impaired phase II metabolism ability in CKD rat. Discussion and conclusion: Glucuronide-sulfate conjugates provide an important clue for further elucidating the activity of conjugated metabolites and their relationship with the nephroprotective efficacy of A. manihot. It is necessary to take caution when extrapolating pharmacokinetics parameters from healthy animals in designing pharmacological studies.

Abelmoschus manihot – a traditional Chinese medicine versus losartan potassium for treating IgA nephropathy: study protocol for a randomized controlled trial

“…Therefore, they can be used for standardization of AM production [20, 21]. Recent studies have indicated that flavonoids can be converted to a combination of acid sulfates in animals, which may be the main active metabolic ingredient for kidney protection [22]. For the mechanistic studies, AM has shown to improve kidney inflammation and glomerular injury in rats with doxorubicin-induced nephropathy through inhibition of the p38 MAPK signaling pathway and TGF-β1 protein expression [23].…”

Quercetin-3-O-β-D-Glucuronide Suppresses Lipopolysaccharide-Induced JNK and ERK Phosphorylation in LPS-Challenged RAW264.7 Cells

“…At the same time, aglycones exhibited potentiated cytotoxicity compared to their glycosides. Recently, it has been suggested that aglycones and glycosides exhibit different pharmacokinetic profile resulting in altered biological efficacy (Guo et al, 2015). Therefore, it is necessary to compare the biological properties of glycosides compared to their aglycones.…”

Treatment of chronic kidney disease using a traditional Chinese medicine, Flos Abelmoschus manihot (Linnaeus) Medicus (Malvaceae)

“…Flavonoids, the primary active components of Flos A. manihot , can be transformed into glucuronide–sulphate conjugates in vivo . The pharmacokinetic profile of these conjugates is of considerable importance to the renoprotective effect of Flos A. manihot in vivo .…”

“…The pharmacokinetic profile of these conjugates is of considerable importance to the renoprotective effect of Flos A. manihot in vivo . The pharmacokinetic profile of conjugated metabolites of Flos A. manihot has been evaluated in normal rats and in adriamycin‐induced CKD rats using UPLC‐MS . In that study, the glucuronide–sulphate conjugates were the major metabolites of Flos A. manihot in normal rats and these metabolites may contribute to the renoprotective effects of Flos A. manihot in vivo .…”

“…In that study, the glucuronide–sulphate conjugates were the major metabolites of Flos A. manihot in normal rats and these metabolites may contribute to the renoprotective effects of Flos A. manihot in vivo . Fewer conjugated metabolites were formed in CKD compared with normal rats . Modification of flavonoids after ingestion, such as conjugation, should not be overlooked in future studies elucidating the efficacy of Flos A. manihot …”