title: Factors limiting the extent of absolute bioavailability of pradefovir in rat.
abstract: 1. Pradefovir was designed as an oral liver target prodrug of 9-(2-phosphonylmethoxyethyl) adenine (PMEA). Liver targeting arises through first pass hepatic metabolism by cytochrome P-450 3A4 (CYP3A4). For CYP3A4 primarily exists in intestines and liver, intestinal metabolism may impair its liver selectivity and oral bioavailability, and then impair its efficacy and safety. It was important to reveal details of the disposition of pradefovir in intestines and liver in a preclinical study. 2. The absolute bioavailability of pradefovir was 4.75% based on the intravenous and oral AUC0-24 h in rats. Pradefovir was stable in intestinal segments and microsomes. The fractions of the dose absorbed from the GI tract were 20.3% and 15.3% from intravenous and oral administration of pradefovir in rats and portal vein-cannulated rat models, respectively. The liver extraction ratio was predicted to be 49.2% from liver microsomes system, based on the monitoring substrate loss rate. Rat intestines' Ussing chamber experiment indicated that P-glycoprotein (P-gp) transporter and paracellular pathway may involve in intestinal transportation. 3. Activation of pradefovir mainly occurs in the liver. Low intestinal absorption was the main reason of low bioavailability of pradefovir in rats. The result was suggestive for the disposition of pradefovir in human intestine and liver.
authors: a Department of Clinical Pharmacy , China Pharmaceutical University , Nanjing , China .
authors: Qingqing
authors: Q
authors: Xiao
authors: b Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China , and.
authors: Wanqiu
authors: W
authors: Yang
authors: b Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China , and.
authors: Dan
authors: D
authors: Wang
authors: b Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China , and.
authors: Lin
authors: L
authors: Chen
authors: b Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China , and.
authors: Linwen
authors: L
authors: Yuan
authors: c Department of Hepatobiliary Surgery , Affiliated Drum Tower Hospital, School of Medicine, Nanjing University , Nanjing , China.
authors: Yitao
authors: Y
authors: Ding
authors: b Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China , and.
authors: Jin
authors: J
authors: Yang
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D009943:Organophosphorus Compounds; D011355:Prodrugs; D051544:Cytochrome P-450 CYP3A; C497721:pradefovir; D000225:Adenine
keywords: Absorption; bioavailability; first-pass metabolism; liver target; pradefovir