title: Toxicokintic and toxicodynamic analysis of clofibrate based on free drug concentrations in nagase analbuminemia rats (NAR).
abstract: Toxicokinetics (TK) is usually performed by measurement of the total drug concentrations in plasma. However, free drug concentrations in plasma are considered to correlate directly with toxicodynamics (TD). In the present study, to evaluate the applicability of TK/TD analysis based on free drug concentrations, we investigated the TK/TD of clofibrate, which binds to albumin with a higher ratio, using an albumin-deficient mutant strain, Nagase analbuminemia rats (NAR). TK, blood chemistry, histopathology, drug and fatty acid metabolizing enzymes and microarray analysis in the liver were examined after a 4-day oral administration of clofibrate. Compared to Sprague-Dawley (SD) rats, the parent strain of NAR, 4.1-fold higher AUC(0-24hr) based on free drug concentrations (3445 versus 844 microg.hr/ml) was observed in NAR when both rats showed the same level of AUC(0-24hr) based on the total drug concentrations (4436 versus 4237microg.hr/ml). Additionally, more severe hepatocellular hypertrophy, increase in aspartate transaminase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), decrease in total cholesterol (T.CHO), phospholipid (PL), triglyceride (TG), and non-esterified fatty acid (NEFA), and increase in the mRNA levels of fatty acid metabolizing enzymes (FAOS, CAT, and CPT) were observed in NAR at the same dose. These results demonstrated that NAR developed more severe toxicities and pharmacological effects than SD rats correlating with the higher AUC of the free drug concentrations. The results also suggested that TK/TD analysis based on the free drug concentration is appropriate to interpret the relationship between exposure and toxicity in cases of protein binding saturation including protein decrease or species differences on protein binding, especially when drugs showing a higher protein binding ratio are dosed.
authors.affiliation: Department of Geriatric Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba. miida.hiroaki.vg@daiichisankyo.co.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miida
authors.forename: Shingo
authors.initials: S
authors.lastname: Arakawa
authors.forename: Yukari
authors.initials: Y
authors.lastname: Shibaya
authors.forename: Kumi
authors.initials: K
authors.lastname: Honda
authors.forename: Naoki
authors.initials: N
authors.lastname: Kiyosawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Watanabe
authors.forename: Sunao
authors.initials: S
authors.lastname: Manabe
authors.forename: Wataru
authors.initials: W
authors.lastname: Takasaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Ueno
mesh_terms: D000818:Animals; D002994:Clofibrate / Q000493:pharmacokinetics* / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D005227:Fatty Acids / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000032:analysis / Q000172:deficiency*
chemical_list: D005227:Fatty Acids; D012709:Serum Albumin; D003577:Cytochrome P-450 Enzyme System; D002994:Clofibrate