Pharmacokinetic Study of Bioactive Flavonoids in the Traditional Japanese Medicine Keigairengyoto Exerting Antibacterial Effects against Staphylococcus aureus

Abstract

Recent studies have demonstrated that flavonoid glucuronides can be deconjugated to the active form aglycone by β-glucuronidase-expressing macrophages. Keigairengyoto (KRT) is a flavonoid-rich traditional Japanese medicine reported to enhance bacterial clearance through immune modulation. Our aims are to examine the pharmacokinetics of KRT flavonoids and to identify active flavonoids contributing to the adjuvant effects of KRT. KRT was evaluated at pharmacokinetic analysis to quantify absorbed flavonoids, and cutaneous infection assay induced in mice by inoculation of Staphylococcus aureus. Preventive or therapeutic KRT administration reduced the number of bacteria in the infection site as well as macroscopic and microscopic lesion scores with efficacies similar to antibiotics. Pharmacokinetic study revealed low plasma levels of flavonoid aglycones after KRT administration; however, plasma concentrations were enhanced markedly by β-glucuronidase treatment, with baicalein the most abundant (Cmax, 1.32 µg/mL). In random screening assays, flavonoids such as bacalein, genistein, and apigenin enhanced bacteria phagocytosis by macrophages. Glucuronide bacalin was converted to aglycone baicalein by incubation with living macrophages, macrophage lysate, or skin homogenate. Taken together, the adjuvant effect of KRT may be due to some blood-absorbed flavonoids which enhance macrophage functions in host defense. Flavonoid-rich KRT may be a beneficial treatment for infectious skin inflammation.

Pharmacokinetics and Metabolism of Naringin and Active Metabolite Naringenin in Rats, Dogs, Humans, and the Differences Between Species

“…Finally, naringin, naringenin, and their conjugates are secreted into bile and excreted into the feces or reabsorbed to become systemically available (i.e., through enterohepatic circulation) (Ma et al, 2006;Liu M. et al, 2012;Zeng et al, 2017). Since the glucuronide and sulphate conjugates of flavonoids were reported as precursors of bioactive metabolites (glycoside or aglycone) (Terao et al, 2011;Matsumoto et al, 2018), hydrolysis with b-glucuronidase is often used in pharmacokinetic studies of naringin or naringenin. Although the metabolism and nonclinical excretion of naringin have previously been reported, enzyme pathways and excretion were insufficiently presented in humans, hindering elucidation of the clinical mechanisms (Liu M. et al, 2012;Zeng et al, 2017).…”

Антибактериальные И Иммуномодулирующие Эффекты Флавоноидов

“…Ïðè ýòîì èçîôëàâîíû îêàçàëèñü íàèáîëåå õîðîøî óñâàèâàåìûìè ôëàâîíîèäàìè, ÷òî ïîçâîëÿåò ïîëàãàòü îá èõ ïåðñïåêòèâå â êà÷åñòâå ëåêàðñòâåííûõ ñðåäñòâ [38]. Ñòîèò îòìåòèòü, ÷òî â íàñòîÿùåå âðåìÿ âåäóòñÿ èññëåäîâàíèÿ ïî óëó÷øåíèþ ôàðìàêîêèíåòèêè ôëàâîíîèäîâ [40], â ÷àñòíîñòè -ïî óâåëè÷åíèþ èõ áèîäîñòóïíîñòè ïðè ïðèåìå âíóòðü [6].…”

“…Íàòèâíûå, à òàêaeå ïðåîáðàçîâàííûå ìèêðîôëîðîé êèøå÷íèêà ôëàâîíîèäû îò÷àñòè âûâîäÿòñÿ ñ êàëîì, äðóãèå, âñàñûâàÿñü, ïîäâåðãàþòñÿ öèòîõðîì Ð-450 (ÑYÐ450)-çàâèñèìîìó ïðåâðàùåíèþ â ýíòåðîöèòàõ è ãåïàòîöèòàõ, ôëàâîíîèä-àãëèêîíû òàêaeå êîíúþãèðóþò ñ ãëþêóðîíîâîé êèñëîòîé, ïîäâåðãàþòñÿ ìåòèëèðîâàíèþ è ñóëüôàòèðîâàíèþ [26]. Ïðèìå÷àòåëüíà ñïîñîáíîñòü îáðàçîâàíèÿ àêòèâíûõ ìåòàáîëèòîâ (àãëèêîíîâ) èç ôëàâîíîèäîâ, öèðêóëèðóþùèõ â ïëàçìå êðîâè â âèäå íåàêòèâíûõ ãëþêóðîíèäîâ, ïðè ëîêàëüíûõ âîñïàëèòåëüíûõ ïîðàaeåíèÿõ çà ñ÷åò ýêñïðåññèðóþùèõ b-ãëþêóðîíèäàçó ìàêðîôàãîâ ("ïàðàäîêñ ôëàâîíîèäîâ") [40], ÷òî ìîaeåò áûòü àêòóàëüíûì äëÿ ðåàëèçàöèè ýôôåêòîâ ôëàâîíîèäîâ ïðè èíôåêöèîííî-âîñïàëèòåëüíîì ïðîöåññå.…”

In Vivo Pharmacokinetic Analysis Utilizing Non-Targeted and Targeted Mass Spectrometry and In Vitro Assay against Transient Receptor Potential Channels of Maobushisaishinto and Its Constituent Asiasari Radix

“…According to past reports, several herbal medicines have been considered as effective for the treatment of infectious disease because herbal medicines exhibit direct bacteriostatic effects and/or stimulate or recruit the host’s innate immune system [ 10 , 11 , 12 ]. Maobushisaishinto (MBST) is a traditional Japanese Kampo medicine (known as Ma-Huang-Fu-Zi-Xi-Xin-Tang in Chinese medicine) that has long been used for treating common upper respiratory tract infections (e.g., the common cold).…”