Impaired 6-hydroxychlorzoxazone elimination in patients with kidney disease: Implication for cytochrome P450 2E1 pharmacogenetic studies.
OBJECTIVE
The purposes of this study were (1) to describe the disposition of chlorzoxazone and 6-hydroxychlorzoxazone in patients with kidney disease, (2) to develop a population pharmacokinetic model including covariates that may influence the pharmacokinetic variability of both compounds, and (3) to examine the effect of covariates on the chlorzoxazone metabolic ratio.


METHODS
Twenty-one subjects received a single oral dose of chlorzoxazone, 250 mg, and plasma and urine samples were collected for up to 120 hours. The impact of creatinine clearance (CL(cr)), age, and weight on chlorzoxazone and 6-hydroxychlorzoxazone clearance terms was assessed with NONMEM software (v.5, level 1.1; Globomax LLC, Hanover, Md) by use of a stepwise backward-elimination technique and the likelihood ratio test.


RESULTS
A linear model with first-order absorption for chlorzoxazone and first-order formation for 6-hydroxychlorzoxazone simultaneously described the disposition of both compounds. Weight was a significant predictor of 6-hydroxychlorzoxazone formation clearance and other, unaccounted for clearance of chlorzoxazone, whereas CL(cr) was a significant predictor of 6-hydroxychlorzoxazone renal clearance. No relationship between CL(cr) and formation clearance was observed. The 6-hydroxychlorzoxazone area under the plasma concentration-time curve was inversely related to CL(cr), even within the range of normal renal function, resulting in chlorzoxazone metabolic ratio values that were substantially higher in subjects with kidney disease. Both the experimental data and model-based Monte Carlo simulations revealed greatly increased chlorzoxazone metabolic ratio values when CL(cr) was low and weight was high.


CONCLUSIONS
Although cytochrome P450 (CYP) 2E1 activity, as estimated by 6-hydroxychlorzoxazone formation clearance, was not affected by kidney disease, the chlorzoxazone metabolic ratio was substantially elevated in these subjects. The results of this study show that the commonly used plasma-based chlorzoxazone metabolic ratio is dependent on renal function and, therefore, does not provide a reliable index of CYP2E1-mediated metabolism.
Nolin
Thomas D
TD
Pharmacodynamic Research Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Gastonguay
Marc R
MR
Bies
Robert R
RR
Matzke
Gary R
GR
Frye
Reginald F
RF
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002753:Chlorzoxazone / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D010597:Pharmacogenetics
D009125:Muscle Relaxants, Central; C039289:6-hydroxychlorzoxazone; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone