1.
Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified.
Pan, LL, Yang, Y, Hui, M, Wang, S, Li, CY, Zhang, H, Ding, YH, Fu, L, Diao, XX, Zhong, DF
Acta pharmacologica Sinica. 2021;(2):311-322
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Abstract
Forsythin extracted from Forsythiae Fructus is widely used to treat fever caused by the common cold or influenza in China, Japan and Korea. The present study aimed to analyze the pharmacokinetics, metabolism and excretion routes of forsythin in humans and determine the major enzymes and transporters involved in these processes. After a single oral administration, forsythin underwent extensive metabolism via hydrolysis and further sulfation. In total, 3 of the 13 metabolites were confirmed by comparison to reference substances, i.e., aglycone M1, M1 sulfate (M2), and M1 glucuronide (M7). Hydrolysis was the initial and main metabolic pathway of the parent compound, followed by extensive sulfation to form M2 and a reduced level of glucuronidation to form M7. In addition, the plasma exposure of M2 and M7 were 86- and 4.2-fold higher than that of forsythin. Within 48 h, ~75.1% of the administered dose was found in urine, with M2 accounting for 71.6%. Further phenotyping experiments revealed that sulfotransferase 1A1 and UDP-glucuronosyltransferase 1A8 were the most active hepatic enzymes involved in the formation of M2 and M7, respectively. The in vitro kinetic study provided direct evidence that M1 showed a preference for sulfation. Sulfated conjugate M2 was identified as a specific substrate of organic anion transporter 3, which could facilitate the renal excretion of M2. Altogether, our study demonstrated that sulfation dominated the metabolism and pharmacokinetics of forsythin, while the sulfate conjugate was excreted mainly in the urine.
2.
Identification of three sulfate-conjugated metabolites of berberine chloride in healthy volunteers' urine after oral administration.
Pan, JF, Yu, C, Zhu, DY, Zhang, H, Zeng, JF, Jiang, SH, Ren, JY
Acta pharmacologica Sinica. 2002;(1):77-82
Abstract
AIM: To identify the structure of unknown metabolites of berberine (Ber) in human urine after oral administration. METHODS Urine samples were obtained from 5 volunteers after they orally took Ber chloride 0.9 g per day for three days. Metabolites in urine samples were isolated and purified by polyporous resin column chromatography. The individual metabolites were identified mainly using electrospray ionization mass spectroscopy (ESI-MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy. RESULTS Three unknown metabolites (M1, M2, and M3) were isolated. They were susceptible to arylsufatase. ESI-MS measurements of M1, M2, and M3 produced quasimolecular ions [M+H]+, m/z 17.9, 404.0, and 402.0 respectively. Especially, each of them produced a characteristic protonated ion [M-80+H]+, which can be ascribed as quasimolecular ions lost a SO3 fragment. 1H NMR spectra of the metabolites were also obtained and each of 1H signals was assigned. CONCLUSION Structures of M1, M2, and M3 were firmly identified as jatrorrhizine-3-sulfate, demethyleneberberine-2-sulfate, and thalifendine-10-sulfate, and the major metabolite was M2.
3.
Sulfate production depicts fed-state adaptation to protein restriction in humans.
Hamadeh, MJ, Schiffrin, A, Hoffer, LJ
American journal of physiology. Endocrinology and metabolism. 2001;(2):E341-8
Abstract
One feature of the adaptation to dietary protein restriction is reduced urea production over the hours after consumption of a test meal of fixed composition. This adaptation is impaired in conventionally treated insulin-dependent diabetes mellitus (Hoffer LJ, Taveroff A, and Schiffrin A. Am J Physiol Endocrinol Metab 272: E59--E67, 1997). We have now tested the response to a test meal containing less protein and included as a main outcome variable the production of sulfate, a specific indicator of sulfur amino acid catabolism. Six normal men consumed a mixed test meal containing 0.25 g protein/kg and 10 kcal/kg while adapted to high (1.5 g x kg(-1) x day(-1)) and low (0.3 g. kg(-1) x day(-1)) protein intakes. They followed the identical protocol twice. Six subjects with insulin-dependent diabetes consumed the test meal while adapted to their customary high-protein diet. Adaptation to protein restriction reproducibly reduced 9-h cumulative postmeal urea N and S production by 22--29% and 49--52%, respectively (both P < 0.05). Similar results were obtained for a postmeal collection period of 6 h. The response of the diabetic subjects was normal. We conclude that reductions in postmeal urea and sulfate production after protein restriction are reproducible and are evident using a postmeal collection period as short as 6 h. Sulfate production effectively depicts fed-state adaptation to protein restriction.