title: Investigation of the rate-determining process in the hepatic elimination of HMG-CoA reductase inhibitors in rats and humans.
abstract: Elucidation of the rate-determining process in the overall hepatic elimination of drugs is critical for predicting their intrinsic hepatic clearance and the impact of variation of sequestration clearance on their systemic concentration. The present study investigated the rate-determining process in the overall hepatic elimination of the HMG-CoA reductase inhibitors pravastatin, pitavastatin, atorvastatin, and fluvastatin both in rats and humans. The uptake of these statins was saturable in both rat and human hepatocytes. Intrinsic hepatic clearance obtained by in vivo pharmacokinetic analysis in rats was close to the uptake clearance determined by the multiple indicator dilution method but much greater than the intrinsic metabolic clearance extrapolated from an in vitro model using liver microsomes. In vivo uptake clearance of the statins in humans (pravastatin, 1.44; pitavastatin, 30.6; atorvastatin, 12.7; and fluvastatin, 62.9 ml/min/g liver), which was obtained by multiplying in vitro uptake clearance determined in cryopreserved human hepatocytes by rat scaling factors, was within the range of overall in vivo intrinsic hepatic clearance (pravastatin, 0.84-1.2; pitavastatin, 14-35; atorvastatin, 11-19; and fluvastatin, 123-185 ml/min/g liver), whereas the intrinsic metabolic clearance of atorvastatin and fluvastatin was considerably low compared with their intrinsic hepatic clearance. Their uptake is the rate-determining process in the overall hepatic elimination of the statins in rats, and this activity likely holds true for humans. In vitro-in vivo extrapolation of the uptake clearance using a cryopreserved human hepatocytes model and rat scaling factors will be effective for predicting in vivo intrinsic hepatic clearance involving active uptake.
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyoku-Tokyo, 113-0033, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kanamaru
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Saito
authors.forename: Zhuohan
authors.initials: Z
authors.lastname: Hu
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000465:Algorithms; D000818:Animals; D001646:Bile / Q000737:chemistry; D001693:Biological Transport, Active; D002851:Chromatography, High Pressure Liquid; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D007201:Indicator Dilution Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D010477:Perfusion; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors