Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride.
The influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reaction was examined in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among the control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was reduced significantly, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentration-time curve was decreased significantly in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G.
Khemawoot
Phisit
P
Department of Medicinal Informatics, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-Machi, Kanazawa, Japan.
Maruyama
Chiharu
C
Tsukada
Hirotaka
H
Noda
Hiroyo
H
Ishizaki
Junko
J
Yokogawa
Koichi
K
Miyamoto
Ken-ichi
K
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity*; D002908:Chronic Disease; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017093:Liver Failure / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008657:Metabolic Clearance Rate; D050217:Metabolic Detoxication, Phase II / Q000502:physiology*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012709:Serum Albumin / Q000378:metabolism; D012712:Serum Globulins / Q000378:metabolism; D014635:Valproic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D000927:Anticonvulsants; D001219:Aspartate Aminotransferases; D002251:Carbon Tetrachloride; D014453:Glucuronosyltransferase; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D012709:Serum Albumin; D012712:Serum Globulins; D014635:Valproic Acid