title: Prodrugs of scutellarin: ethyl, benzyl and N,N-diethylglycolamide ester synthesis, physicochemical properties, intestinal metabolism and oral bioavailability in the rats.
abstract: In an effort to enhance the oral bioavailability of scutellarin, ethyl, benzyl and N,N-diethylglycolamide ester of scutellarin were synthesized. The hydrolysis of the prodrugs follows first-order kinetics in aqueous solution, and produced a V-shaped pH profile. The N,N-diethylglycolamide ester is highly susceptible to enzymatic hydrolysis in human plasma (t(1/2) approximately 7 min) with a high stability in aqueous solution (t(1/2) approximately 16 day, pH 4.2). Compared with the solubility of scutellarin, the solubility of glycolamide ester was about ten times in pH 4.0 buffer, and about thirty five times in water. Its apparent partition coefficient increased significantly from -2.56 to 1.48. Glycolamide ester of scutellarin was chosen to investigate the intestinal metabolism and in vivo bioavailability. Degradation studies in the intestinal tract content and homogenates indicated intestinal metabolism before absorption was a crucial obstacle for the prodrug. N,N-Diethylglycolamide ester can be protected from the degradation in the intestinal lumen by an emulsion. A significant increase in the plasma AUC and C(max) of the prodrug emulsion was observed in rats, compared with that of the scutellarin-cyclodextrin complex (P<0.01). The emulsion of N,N-diethylglycolamide ester produces a 1.58-fold enhancement in apparent bioavailability and 1.4-fold increase in the absolute bioavailability compared to the scutallarin-cyclodextrin complex.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Cao
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Guo
authors.forename: Qi-Neng
authors.initials: QN
authors.lastname: Ping
authors.forename: Zheng-Gen
authors.initials: ZG
authors.lastname: Liao
mesh_terms: D000818:Animals; D047310:Apigenin / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D003505:Cyclodextrins / Q000737:chemistry; D047309:Flavones / Q000138:chemical synthesis / Q000493:pharmacokinetics; D005766:Gastrointestinal Contents; D005965:Glucuronates / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D020719:Glucuronides / Q000138:chemical synthesis / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D003505:Cyclodextrins; D047309:Flavones; D005965:Glucuronates; D020719:Glucuronides; C517532:N,N-diethylglycolamide-4',5,6-trihydroxyflavone-7-glucuronide ester; D011355:Prodrugs; C517530:benzyl scutellarin; C517531:ethyl scutellarin; C484876:scutellarin; D047310:Apigenin