Impaired 6-hydroxychlorzoxazone elimination in patients with kidney disease: Implication for cytochrome P450 2E1 pharmacogenetic studies

Thomas D. Nolin, Marc R. Gastonguay, Robert Bies, Gary R. Matzke, Reginald F. Frye

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 (CLcr), 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 CLcr was a significant predictor of 6-hydroxychlorzoxazone renal clearance. No relationship between CLcr. and formation clearance was observed. The 6-hydroxychlorzoxazone area under the plasma concentration-time curve was inversely related to CLcr, 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 CLcr 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.

Original languageEnglish (US)
Pages (from-to)555-568
Number of pages14
JournalClinical Pharmacology and Therapeutics
Volume74
Issue number6
DOIs
StatePublished - Dec 2003
Externally publishedYes

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Chlorzoxazone
Cytochrome P-450 CYP2E1
Kidney Diseases
Kidney
Weights and Measures
Pharmacokinetics
6-hydroxychlorzoxazone
Pharmacogenomic Testing
Linear Models
Creatinine
Reference Values
Theoretical Models
Software

ASJC Scopus subject areas

  • Pharmacology

Cite this

Impaired 6-hydroxychlorzoxazone elimination in patients with kidney disease : Implication for cytochrome P450 2E1 pharmacogenetic studies. / Nolin, Thomas D.; Gastonguay, Marc R.; Bies, Robert; Matzke, Gary R.; Frye, Reginald F.

In: Clinical Pharmacology and Therapeutics, Vol. 74, No. 6, 12.2003, p. 555-568.

Research output: Contribution to journalArticle

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title = "Impaired 6-hydroxychlorzoxazone elimination in patients with kidney disease: Implication for cytochrome P450 2E1 pharmacogenetic studies",
abstract = "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 (CLcr), 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 CLcr was a significant predictor of 6-hydroxychlorzoxazone renal clearance. No relationship between CLcr. and formation clearance was observed. The 6-hydroxychlorzoxazone area under the plasma concentration-time curve was inversely related to CLcr, 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 CLcr 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.",
author = "Nolin, {Thomas D.} and Gastonguay, {Marc R.} and Robert Bies and Matzke, {Gary R.} and Frye, {Reginald F.}",
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T1 - Impaired 6-hydroxychlorzoxazone elimination in patients with kidney disease

T2 - Implication for cytochrome P450 2E1 pharmacogenetic studies

AU - Nolin, Thomas D.

AU - Gastonguay, Marc R.

AU - Bies, Robert

AU - Matzke, Gary R.

AU - Frye, Reginald F.

PY - 2003/12

Y1 - 2003/12

N2 - 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 (CLcr), 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 CLcr was a significant predictor of 6-hydroxychlorzoxazone renal clearance. No relationship between CLcr. and formation clearance was observed. The 6-hydroxychlorzoxazone area under the plasma concentration-time curve was inversely related to CLcr, 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 CLcr 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.

AB - 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 (CLcr), 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 CLcr was a significant predictor of 6-hydroxychlorzoxazone renal clearance. No relationship between CLcr. and formation clearance was observed. The 6-hydroxychlorzoxazone area under the plasma concentration-time curve was inversely related to CLcr, 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 CLcr 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.

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