Pharmacokinetics and Safety of DW1029M, a Botanical Drug for the Treatment of Diabetic Nephropathy, Following Single Doses in Healthy Subjects

Kim, Yun-Jeong; Jeon, Ji‐Young; Kim, Eun Young; Lim, Cheol-Hee; Jang, Hwan Bong; Kim, Min‐Gul

doi:10.1002/cpdd.343

Cited by 5 publications

(3 citation statements)

References 30 publications

(44 reference statements)

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“…The silkworm midgut is the central tissue for nutrient absorption; furthermore, it serves as a barrier to prevent exogenous substances from entering the cells. Mulberry leaves contain polyphenols such as quercetin, apigenin, resveratrol, daidzein, and genistein [16][17][18][19][20], all of which have biological activity. For example, quercetin is used as an antioxidant to reduce the immunosuppressive effects of hyperglycemic sera in patients with type 2 diabetes [21].…”

Section: Plos Onementioning

confidence: 99%

Novel silkworm (Bombyx mori) sulfotransferase swSULT ST3 is involved in metabolism of polyphenols from mulberry leaves

et al. 2022

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Polyphenols in plants are important for defense responses against microorganisms, insect herbivory, and control of feeding. Owing to their antioxidant, anti-cancer, and anti-inflammatory activities, their importance in human nutrition has been acknowledged. However, metabolism of polyphenols derived from mulberry leaves in silkworms (Bombyx mori) remains unclear. Sulfotransferases (SULT) are involved in the metabolism of xenobiotics and endogenous compounds. The purpose of this study is to investigate the metabolic mechanism of polyphenols mediated by B. mori SULT. Here, we identified a novel SULT in silkworms (herein, swSULT ST3). Recombinant swSULT ST3 overexpressed in Escherichia coli effectively sulfated polyphenols present in mulberry leaves. swSULT ST3 showed high specific activity toward genistein among the polyphenols. Genistein-7-sulfate was produced by the activity of swSULT ST3. Higher expression of swSULT ST3 mRNA was observed in the midgut and fat body than in the hemocytes, testis, ovary, and silk gland. Polyphenols inhibited the aldo-keto reductase detoxification of reactive aldehydes from mulberry leaves, and the most noticeable inhibition was observed with genistein. Our results suggest that swSULT ST3 plays a role in the detoxification of polyphenols, including genistein, and contributes to the effects of aldo-keto reductase in the midgut of silkworms. This study provides new insight into the functions of SULTs and the molecular mechanism responsible for host plant selection in lepidopteran insects.

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Section: Plos Onementioning

confidence: 99%

Novel silkworm (Bombyx mori) sulfotransferase swSULT ST3 is involved in metabolism of polyphenols from mulberry leaves

et al. 2022

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“…Diabetic nephropathy (DN), a chronic and grave complication in patients with diabetes, has shown an escalating incidence in China and is currently considered to be the primary cause of end‐stage renal disease. [ 1–3 ] The etiology of DN remains elusive, although it is believed to be related to genetic factors, [ 4,5 ] metabolic abnormalities triggered by hyperglycemia, [ 6–8 ] and hypertension. [ 9–11 ] DN is characterized by distinctive histological changes, including mesangial sclerosis (diffuse or nodular), thickening of glomerular and tubular basement membranes, and exudative lesions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and activity of arylcoumarin derivatives with therapeutic effects on diabetic nephropathy

Pan,

Zhou,

Liu

et al. 2023

Archiv der Pharmazie

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In the literature, daidzein has been reported to exhibit cardiovascular protective effects and hypoglycemic activity in mice. We sought to design and synthesize a novel compound, SJ‐6, an analog of daidzein, with improved hypoglycemic properties. Although SJ‐6 demonstrated favorable hypoglycemic effects, its pharmacokinetic limitations prompted us to design and synthesize prodrugs of SJ‐6. We conducted a comprehensive evaluation of the prodrugs, including in vitro and in vivo studies, such as cytotoxicity, absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulation analysis, in vitro blood–brain barrier (BBB) permeability evaluation, compound effect on insulin resistance, oral glucose tolerance test (OGTT), in vivo plasma concentration testing, acute toxicity test in rats, and long‐term gavage administration experiment. Furthermore, we examined the antidiabetic nephropathy activity of our lead compound, compound 10, which demonstrated superior efficacy compared with the positive control drug, metformin hydrochloride. Our findings suggest that compound 10 represents a promising lead compound for the prevention and treatment of diabetic nephropathy.

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“…The repeated oral administration of 50 and 250 mg/kg/day of PUE for 30 days in rats showed no changes in hematological and biochemical parameters (Chung et al, 2009). A single oral administration of 6, 12, or 24 mg/kg of PUE in healthy Korean subjects indicated no clinically significant changes and no serious adverse effects on of vital signs (Kim et al, 2017).…”

Section: Toxicity Of Puerarinmentioning

confidence: 90%

Comparative pharmacokinetics of puerarin in pure compound form and puerarin in white kwao krua extract in female cynomolgus monkeys

Namken

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Pueraria mirifica is an endemic Thai plant that puerarin is a major chemical found in this plant and shows several pharmacological activities in aging diseases. Although the pharmacokinetic data on puerarin have been reported in rodents, it is still inconclusive for the development of puerarin as phytopharmaceutical products for human use. This is because of the differences in anatomical and physiological characteristics between rodents and humans. Therefore, the comparative pharmacokinetics of puerarin in pure compound form (PUE) and puerarin in P. mirifica extract (PME) was conducted in female cynomolgus monkeys. PME at a dose of 826 mg/kg.BW (equivalent to 10 mg/kg.BW of puerarin) and PUE at a dose of 10 mg/kg.BW were daily orally administered to monkeys for 7 consecutive days. A single intravenous injection of 1 mg/kg.BW of PUE was also performed for the bioavailability analysis of puerarin orally administered to monkeys. Serial blood samples and excreta (urine and feces) were collected after dosing at designated times. The levels of puerarin in biological samples were determined by liquid chromatography tandem mass spectrometry. After PME and PUE orally dosing to monkeys, plasma levels of aspartate aminotransferase and alanine aminotransferase which were indicated the liver function, and plasma creatinine levels which were indicated the kidney function were fluctuated in the normal range, with no abnormal physical signs in animals. The absolute oral bioavailability of puerarin was 1.44% after the PME oral dosing and 0.88% after the PUE oral dosing, but the T1/2 was prolonged for nearly two times in the PUE group (4.78 h) comparing to the PME group (2.61 h). After 7-day multiple oral dosing of puerarin in both preparations, the accumulations were occurred in the body of the animals. Major metabolite pathways of puerarin found in monkeys were hydroxylation and deglycosylation before excreted via urine and feces. A negligible amount of unchanged puerarin was detected for less than 1% in urine and feces. In conclusion, an oral dosing of a puerarin shows the better absorption in the extract form than in the pure compound form, but it has a shorter half-life. Puerarin can be accumulated in the body of the animals when it is continuously orally dosing. Thus, the pharmacokinetic profiles obtained from female cynomolgus monkeys in this study could help to design the prescribed remedy of the oral administration of puerarin as phytopharmaceutical products for human use.

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Pharmacokinetics and Safety of DW1029M, a Botanical Drug for the Treatment of Diabetic Nephropathy, Following Single Doses in Healthy Subjects

Cited by 5 publications

References 30 publications

Novel silkworm (Bombyx mori) sulfotransferase swSULT ST3 is involved in metabolism of polyphenols from mulberry leaves

Novel silkworm (Bombyx mori) sulfotransferase swSULT ST3 is involved in metabolism of polyphenols from mulberry leaves

Synthesis and activity of arylcoumarin derivatives with therapeutic effects on diabetic nephropathy

Comparative pharmacokinetics of puerarin in pure compound form and puerarin in white kwao krua extract in female cynomolgus monkeys

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