| Andrographolide is one of principal constituents of a famous traditional Chinese herbal medicine Andrographis paniculate (Burm) Nees. Its chemical structure is 3-[2-[decahydro-6-hydroxy-5-(hydroxymethyl)-5,8a-dime1hyl-2-methylene-l-napthalenyl] ethylidene] dihydro-4-hydroxy-2(3H)-furanone. It has many bioactivities, such as anti-inflammation, anti-allergic, anti-platelet aggregation, hepatoprotective anti-human immunodeficiency virus (HIV) and anti-cancer activities. And this compound has been widely used in clinic for the treatment of fever, cold, inflammation, diarrhea and other infectious diseases. But there are little reports about its metabolic information research in humans.In the previous study, ten metabolites were isolated from rat urine and feces after oral administration. Among them, one metabolite, 14-deoxy-12-sulfo-andrographolide, was found to be identical to an antiinflammatory drug (Lianbizhi) currently being used in clinic as injection. In order to clarify its metabolic information in humans, we further investigated the metabolites of andrographolide in humans.A total of 23 metabolites were obtained from human urine and the structures of 18 metabolites were determined unambiguously by means of chemical and spectral analyses. All of these 18 metabolites are not only new metabolites of andrographolide, but also new compounds. The structures of another 2 metabolites were deduced on the basis of the 13C-NMR spectral data and MS" fragment ions rules.The structures of metabolites 1 to 18 were determined as: Andrographolide- 19-O-B-D-glucuronide (M-1), Isoandrographolide-19-O-B-D-glucuronide (M-2), 14-Deoxy-12-hydroxy-andrographolide-19-O-B-D-glucuronide(M-3), Andrographolide-19-O-B-D-[6-methyl-glucuronide] (M-4), 3-oxo-andrographolide-19-0-B-D-glucuronide (M-5),14-Deoxy-12(13)-en-andrographolide- 1 9-O-B-D-glucuronide, (M-6), 1 4-Deoxy-andrographolide- 1 9-0-B-D-glucuronide (M-7), Andrographolide-3-O-sulfate (M-8), Isoandrographolide-3-O-sulfate (M-9), 14-Deoxy-andrographolide-3-Osulfate (M-10), 14-Deoxy-12-(cysteine-S-yl)-andrographolide-3-0-sulfate (M-11), 14-Deoxy-12-carbamido-andrographolide (M-12) , 14-Deoxy-12-carbamido-andrographolide-19-O-sulfate(M-13), 14-Deoxy-12(R/S)-carbamido-andrographolide-19-O-B-D-glucuronide (M-14), 14-Deoxy-12(S/R)-carbamido-andrographolide-19-O-B-D-glucuronide(M-15) , 14-Deoxy-12(R/S)-(creatinine-5-yl)-andrographolide-19-O-B-D-glucuronide (M-16) , 14-Deoxy-12(S/R)-(creatinine-5-yl)-andrographolide-19-O-B-D-glucuronide (M-17) , 17-Hydro-1 4-deoxy-8(S)-hydroxy- 1 2(R/S)-(hydrazine-yl)-andrographolide- 19-O-B-D-glucuronide (M-18). The structures of metabolites 19 and 20 were deduced as: 17-Hydro-14-deoxy-8(S)-hydroxy-12(S/R)-Chydrazme-yO-andrographolide-19-O-B-D-glucuronide (M-19) and 14/19-O-Methyl-andrographolide-3-O-sulfate (M-20)oThis study demonstrates that andrographolide is extensively metabolized by a variety of routes to form a large number of metabolites in humans. The routes include oxidation, hydrolysis, isomerization, glucuronidation, sulfataion, and the conjugation of urea, cysteine, creatinine, hydrazine.Moreover, two new metabolic reactions-the adduction of andrographolide with creatinine and hydrazine, and a rare metabolic reaction-the adduction of andrographolide with carbamide, were found in this study. The mechanism of these reactions was presumed that p-carbon of a, p-unsaturated carbonyl compounds were attacked by nitrogen atom or carbanion which had lone-pair electrons and formed these adducts, and at the same time, the hydroxyl group at position 14 was dehydrated and a new carbon-carbon double bond was formed at 1 4( 1 3).In addition, obvious metabolic species difference between humans and rats was found in the study as well, In rats, sulfonate and sulfate conjugate are two types of main metabolites, while in humans, glucuronide, sulfate and urea adducts are principle metabolites.In conclusion, this study elucidated the metabolites and metabolic pathways of andrographolide in humans and provided the academic evidence...
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