title: Prediction of human pharmacokinetics from preclinical information of rhein, an antidiabetic nephropathy drug, using a physiologically based pharmacokinetic model.
abstract: The aim of the study was to develop a physiologically based pharmacokinetic (PBPK) model of rhein to predict human pharmacokinetics before dosing for the first time in human beings. After oral administration of rhein at the doses of 35, 70 and 140 mg/kg in rat, rhein had the following mean plasma pharmacokinetic properties: t1/2 of 3.2, 3.6 and 4.3 hr, AUC∞ of 69.5, 164.3 and 237.8 μg/h/ml and CL/F of 503.4, 426.1 and 588.8 ml/hr/kg, respectively. In vitro, the intrinsic clearance (Clint ) of rhein in cytochrome P450 (CYP450), UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) metabolism of rat was 0.6, 7.8, and 5.5 μl/min/mg protein, respectively. The Clint of rhein in CYP450, UGT and SULT of human beings was 0.10, 1.36 and 0.68 μl/min/mg protein. The rat pharmacokinetics and the metabolism data in vitro were used to construct the PBPK model of rhein, and the observed plasma drug concentration profiles of rhein in rat were validated by a PBPK model. Subsequently, the plasma drug concentration profiles of human beings by the present PBPK model were validated by experimental data in human beings accurately.
authors.affiliation: State Key Laboratory of Natural Medicines, Key Lab of Drug Metabolism & Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Hao
authors.forename: Qu
authors.initials: Q
authors.lastname: Qi
authors.forename: Ping
authors.initials: P
authors.lastname: Wan
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.forename: Jianguo
authors.initials: J
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D051381:Rats; D015203:Reproducibility of Results; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D000880:Anthraquinones; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D015238:Sulfotransferases; C020491:rhein