PMID- 18670166
OWN - NLM
STAT- MEDLINE
DCOM- 20081028
LR  - 20190911
IS  - 1880-3989 (Electronic)
IS  - 0388-1350 (Linking)
VI  - 33
IP  - 3
DP  - 2008 Aug
TI  - Toxicokintic and toxicodynamic analysis of clofibrate based on free drug 
      concentrations in nagase analbuminemia rats (NAR).
PG  - 349-61
AB  - 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.
FAU - Miida, Hiroaki
AU  - Miida H
AD  - Department of Geriatric Pharmacology and Therapeutics, Graduate School of 
      Pharmaceutical Sciences, Chiba University, Chiba. 
      miida.hiroaki.vg@daiichisankyo.co.jp
FAU - Arakawa, Shingo
AU  - Arakawa S
FAU - Shibaya, Yukari
AU  - Shibaya Y
FAU - Honda, Kumi
AU  - Honda K
FAU - Kiyosawa, Naoki
AU  - Kiyosawa N
FAU - Watanabe, Kyoko
AU  - Watanabe K
FAU - Manabe, Sunao
AU  - Manabe S
FAU - Takasaki, Wataru
AU  - Takasaki W
FAU - Ueno, Koichi
AU  - Ueno K
LA  - eng
PT  - Journal Article
PL  - Japan
TA  - J Toxicol Sci
JT  - The Journal of toxicological sciences
JID - 7805798
RN  - 0 (Fatty Acids)
RN  - 0 (Serum Albumin)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - HPN91K7FU3 (Clofibrate)
SB  - IM
MH  - Animals
MH  - Clofibrate/*pharmacokinetics/*toxicity
MH  - Cytochrome P-450 Enzyme System/analysis
MH  - Fatty Acids/metabolism
MH  - Male
MH  - Protein Binding
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Serum Albumin/analysis/*deficiency
EDAT- 2008/08/02 09:00
MHDA- 2008/10/29 09:00
CRDT- 2008/08/02 09:00
PHST- 2008/08/02 09:00 [pubmed]
PHST- 2008/10/29 09:00 [medline]
PHST- 2008/08/02 09:00 [entrez]
AID - JST.JSTAGE/jts/33.349 [pii]
AID - 10.2131/jts.33.349 [doi]
PST - ppublish
SO  - J Toxicol Sci. 2008 Aug;33(3):349-61. doi: 10.2131/jts.33.349.