Human Pharmacokinetic Prediction of UDP-Glucuronosyltransferase Substrates with an Animal Scale-Up Approach

• DOI: 10.1124/dmd.110.037457
• Publication Date: 2011-02-01T03:36:39Z
• Authors: Tsuneo Deguchi; Nobuaki Watanabe; Atsushi Kurihara; Katsuhiro Igeta; Hidenori Ikenaga; Keiichi Fusegawa; Norio Suzuki; Shinji Murata; Masakazu Hirouchi; Yoshitake Furuta; Masaru Iwasaki; Osamu Okazaki; Takashi Izumi
• Keywords: Allometry; Animal Species

The aim of the current study was to evaluate accuracy allometric scaling methods for drugs metabolized by UDP-glucuronosyltransferases (UGTs), such as ketoprofen, imipramine, lorazepam, levofloxacin, zidovudine, diclofenac, furosemide, raloxifene, gemfibrozil, mycophenolic acid, indomethacin, and telmisartan. Human plasma clearance (CL) predictions were conducted from preclinical in vivo data using multiple-species allometry with rule exponents single-species (SSS) mice, rats, monkeys, or dogs. Distribution volume at a steady state (<i>V</i>_ss) predicted SSS <i>V</i>_ss. Oral (CL_po) calculated under assumption that <i>F</i>_a × <i>F</i>_g equivalent across species. Each results compared observed parameter clinical after intravenous oral administration. Multiple-species dogs resulted similar CL CL_po predictions. Monkeys tended provide most accurate human CL_po. ability predict half-life, which determined <i>V</i>_ss predictions, more rats monkeys. fraction glucuronidation (<i>f</i>_m,UGT) bile duct-cannulated monkeys relatively humans other animal species, likely contributed highest prediction On basis results, would be reliable than species predicting pharmacokinetics <i>f</i>_m,UGT UGTs.