title: Pharmacokinetics in Vitro and in Vivo of Two Novel Prodrugs of Oleanolic Acid in Rats and Its Hepatoprotective Effects against Liver Injury Induced by CCl4.
abstract: Oleanolic acid (OA) is a well-known pentacyclic triterpenoid compound, which has been used as a dietary supplement and is supplied as an over-the-counter drug for the treatment of human liver diseases. These are reasons for the low bioavailability of OA which have restricted its wider application. In this study, two OA prodrugs (1,3-cyclic propanyl phosphate esters of OA) were designed and synthesized. The hepatoprotective effects of these prodrugs were evaluated against carbon tetrachloride (CCl4) induced liver injury in mice; the levels of alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and aspartate aminotransferase (AST) were significantly increased, and the level of the hepatic malondialdehyde (MDA) was increased. The metabolism, in vitro, of the prodrugs was studied by incubation in rat liver microsome; the plasma pharmacokinetics and the biodistribution in vivo after intravenous (iv) injection to six rats were investigated, respectively. The prodrugs diminished gradually with time; most of the parent drugs were released within 30 min in vitro, and the presumed mechanism of the in vitro metabolism was confirmed. The plasma-concentration data in vivo was analyzed by a compartmental method: both the prodrugs and the corresponding released parent drugs existed at up to 48 h in rats. The t1/2 improved after intravenous administration in rats compared with direct injection of the parent drugs. All analyte concentrations were highest in the liver, and most of the prodrugs were excreted in feces (>47.11%). Therefore, 1,3-cyclic propanyl phosphate esters of OA can serve as a promising lead candidate for drugs.
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education of China, School of Pharmacy, Ocean University of China , Qingdao 266003, P. R. China.
authors.forename: Zongjiang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: CAS Key Laboratory of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences , Qingdao 266101, China.
authors.forename: Weizhi
authors.initials: W
authors.lastname: Sun
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education of China, School of Pharmacy, Ocean University of China , Qingdao 266003, P. R. China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Peng
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education of China, School of Pharmacy, Ocean University of China , Qingdao 266003, P. R. China.
authors.forename: Rilei
authors.initials: R
authors.lastname: Yu
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education of China, School of Pharmacy, Ocean University of China , Qingdao 266003, P. R. China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Li
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education of China, School of Pharmacy, Ocean University of China , Qingdao 266003, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009828:Oleanolic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020011:Protective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D011355:Prodrugs; D020011:Protective Agents; D008315:Malondialdehyde; D009828:Oleanolic Acid; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: biodistribution; hepatoprotective; oleanolic acid (OA); pharmacokinetics; prodrug