Effects of acute renal failure on the pharmacokinetics of chlorzoxazone in rats.
The purpose of this study is to report the changes of CYP2E1, CYP1A2, CYP2B1/2, CYP2C11, CYP3A23, and CYP3A2 expression and pharmacokinetics and tissue distribution of chlorzoxazone (CZX) and 6-hydroxychlorzoxazone (OH-CZX) in rats with acute renal failure induced by uranyl nitrate (U-ARF), and the role of CYP3A23 and CYP3A2 in the formation of OH-CZX in rats with U-ARF. In rats with U-ARF, CYP2C11 decreased to 20% of control, whereas CYP2E1 and CYP3A23 increased 2.3 and 4 times, respectively, compared with control. But expression of CYP1A2 and CYP2B1/2 was not changed by U-ARF. After i.v. administration of CZX at a dose of 20 mg/kg to rats with U-ARF, the areas under the plasma concentration-time curve from time 0 to time infinity (AUCs) of CZX and OH-CZX were significantly smaller and greater, respectively, than those in control rats. In rats with U-ARF, CZX was below the detection limit at 120 min in all rat tissues studied, whereas it was detected in all tissues of control rats at both 30 and 120 min. However, in control rats, OH-CZX was below the detection limit at both 30 and 120 min in all rat tissues except kidney, whereas it was detected in all tissues of rats with U-ARF at both 30 and 120 min. Based on results from supporting experiments with DDT and 2,2-bis(4-chlorophenyl)1,1-dichloroethylene treatment of rats, the contribution of CYP3A23 and CYP3A2 to the enhanced formation of OH-CZX in rats with U-ARF is likely to be negligible.
Moon
Young Jin
YJ
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Lee
Ae Kyung
AK
Chung
Hye Chin
HC
Kim
Eun Jung
EJ
Kim
So Hee
SH
Lee
Duk Chul
DC
Lee
Inchul
I
Kim
Sang Geon
SG
Lee
Myung Gull
MG
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D015152:Blotting, Northern; D002753:Chlorzoxazone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004790:Enzyme Induction; D015870:Gene Expression; D015151:Immunoblotting; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014502:Uranyl Nitrate / Q000633:toxicity
D012333:RNA, Messenger; D014502:Uranyl Nitrate; C039289:6-hydroxychlorzoxazone; D001189:Aryl Hydrocarbon Hydroxylases; D002753:Chlorzoxazone