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Urinary excretion of 6‐hydroxychlorzoxazone as an index of CYP2E1 activity
Author(s) -
Dreisbach Albert W.,
Ferencz Nicholas,
Hopkins Nancy Eddy,
Fuentes Maria G.,
Rege Arvind B.,
George William J.,
Lertora Juan J. L.
Publication year - 1995
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/0009-9236(95)90169-8
Subject(s) - excretion , urinary system , index (typography) , medicine , urology , chemistry , computer science , world wide web
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 3½, 4½, 5½, and 6½ 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 (K e ) and urinary excretion of the metabolite ( n = 27, r = 0.42, p < 0.03) and a significant negative correlation between plasma K e 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 K e of 0.57 ± 0.17 hr −1 for the full kinetic studies. The formation clearance of the 6‐hydroxy metabolite was negatively correlated with HI ( n = 10, r = −0.67, p < 0.04). There was also a significant positive correlation between plasma K e 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. Clinical Pharmacology & Therapeutics (1995) 58 , 498–505; doi: