Urinary excretion of 6-hydroxychlorzoxazone as an index of CYP2E1 activity.
OBJECTIVE
To determine whether the urinary excretion of 6-hydroxychlorzoxazone is an index of CYP2E1 activity in vivo.


METHODS
Male volunteers (n = 27; age range, 17 to 36 years) who were abstinent from alcohol were studied. Chlorzoxazone, 500 mg, was given orally and plasma was collected at 31/2, 41/2, 51/2, and 61/2 hours after dosing. Urine was collected for 8 hours. Ten volunteers participated in full kinetic studies to define the absorption phase and plasma area under the concentration-time curve of chlorzoxazone and the urinary kinetics of the 6-hydroxy metabolite. Chlorzoxazone and the 6-hydroxy metabolite were measured by high-performance liquid chromatography. CYP2E1 activity was expressed as a hydroxylation index (HI = mmole oral chlorzoxazone dose/mmole 6-hydroxychlorzoxazone in 8-hour urine).


RESULTS
There was a significant positive correlation between plasma elimination rate constant for chlorzoxazone (Ke) and urinary excretion of the metabolite (n = 27, r = 0.42, p < 0.03) and a significant negative correlation between plasma Ke and HI (n = 27, r = -0.41, p < 0.04). The mean absorption rate constant for chlorzoxazone of 3.11 +/- 4.67 hr-1 was fivefold greater than the plasma Ke of 0.57 +/- 0.17 hr-1 for the full kinetic studies. The formation clearance of the 6-hydroxy metabolite was negative between plasma Ke of the parent compound and disposition rate constant for urinary excretion of the 6-hydroxy metabolite (n = 15, r = 0.85, p < 0.0001).


CONCLUSIONS
The urinary excretion of 6-hydroxychlorzoxazone is limited by formation rate and may be useful as an in vivo probe of CYP2E1 activity.
Dreisbach
A W
AW
Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Ferencz
N
N
Hopkins
N E
NE
Fuentes
M G
MG
Rege
A B
AB
George
W J
WJ
Lertora
J J
JJ
D000293:Adolescent; D000328:Adult; D002753:Chlorzoxazone / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008297:Male; D009125:Muscle Relaxants, Central / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*
D009125:Muscle Relaxants, Central; C039289:6-hydroxychlorzoxazone; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; D002753:Chlorzoxazone