Hepatic disposition of the cytochrome P450 2E1 marker chlorzoxazone and its hydroxylated metabolite in isolated perfused rat livers.
The steady-state disposition of chlorzoxazone (CZX) and its hydroxylated metabolite 6-hydroxychlorzoxazone (HCZX) was determined in a single-pass isolated perfused rat liver (IPRL) model using constant CZX concentrations of 10-200 microM. The concentrations of CZX, HCZX, and/or HCZX glucuronide in the perfusate, bile, and liver tissues were measured and kinetic parameters calculated. Upon an increase in CZX inlet concentrations from 10 to 200 microM, its extraction ratio sharply declined from 0.681 to 0.087. This was associated with a saturable formation of HCZX, which was rapidly and completely metabolized to its glucuronide conjugate. Whereas the biliary excretion of CZX was negligible, that of HCZX was substantial (up to 40% of the generated metabolite). Overall, 79-93% of the CZX dose (10-200 microM) was recovered in our model as CZX and HCZX. Additionally, HCZX accounted for 56% (200 microM) to 71% (10 microM) of the extracted CZX dose. Further, a preliminary study using the preformed HCZX showed a complete (100%) recovery of the metabolite as its conjugate. Therefore, the unrecovered portion of CZX dose in our study (7-21% of the administered dose or 29-44% of the extracted dose at inlet CZX concentrations of 10-200 microM) is most likely due to parallel metabolism of CZX to other metabolites.
Mehvar
Reza
R
School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter, Amarillo, USA. reza.mehvar@ttuhsc.edu
Vuppugalla
Ragini
R
D000818:Animals; D001646:Bile / Q000737:chemistry; D015415:Biomarkers; D002753:Chlorzoxazone / Q000031:analogs & derivatives* / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D009125:Muscle Relaxants, Central / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D015415:Biomarkers; D009125:Muscle Relaxants, Central; C039289:6-hydroxychlorzoxazone; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone