Disease relevance of chlorzoxazone

• Chlorzoxazone-induced spasmotic torticollis [1].
• Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone [2].
• By contrast, obesity resulted in significant increases in the oral clearance and distribution of chlorzoxazone on both an absolute and weight-normalized basis; for example, 4.15 +/- 0.81 versus 6.23 +/- 1.72 ml.min-1.kg-1 and 0.50 +/- 0.28 versus 0.82 +/- 0.19 L.kg-1 [3].
• However, serious to morbid obesity in humans is associated with increased 6-hydroxylation of chlorzoxazone, consistent with induction of CYP2E1 [3].
• 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 [4].

Psychiatry related information on chlorzoxazone

• Effects of glucose supplementation on the pharmacokinetics of intravenous chlorzoxazone in rats with water deprivation for 72 h [5].

High impact information on chlorzoxazone

• Intravenous and oral midazolam (MDZ) clearances were used to measure the in vivo CYP3A activity, and chlorzoxazone (CHZ) oral clearance was used to assess in vivo CYP2E1 activity [6].
• CYP2E1 and NQO1 genotypes were determined by PCR-RFLP, and CYP2E1 enzymatic activity was estimated by the fractional excretion of chlorzoxazone (fe(6-OH)) for 50 cases of BP and 50 controls [2].
• Of the 52 substrates for the enzyme identified in this review, the demethylation of N,N-dimethylnitrosamine and the hydroxylation of p-nitrophenol and chlorzoxazone are the most effective for monitoring the level of this enzyme [7].
• Chlorzoxazone was not a substrate for iNOS but was a potent competitive inhibitor with respect to L-Arg with Ki = 3.3+/-0.7 microM [8].
• Characterization of inducible nitric-oxide synthase by cytochrome P-450 substrates and inhibitors. Inhibition by chlorzoxazone [8].

Chemical compound and disease context of chlorzoxazone

• Kinetics of drug action in disease states. XXVII. Effect of experimental renal failure on the pharmacodynamics of zoxazolamine and chlorzoxazone [9].
• Effects of glucose on the pharmacokinetics of intravenous chlorzoxazone in rats with acute renal failure induced by uranyl nitrate [10].
• Effects of recombinant human growth hormone on the pharmacokinetics of intravenous chlorzoxazone in rats with acute renal failure induced by uranyl nitrate [11].
• In addition, chlorzoxazone and trimethadione metabolism are good CYP2E1 probes for liver disease in vivo and in vitro [12].

Biological context of chlorzoxazone

• Twenty-one healthy volunteers were recruited for CYP2E1 phenotype study using a chlorzoxazone test [13].
• The effect of endotoxin administration on the pharmacokinetics of chlorzoxazone in humans [14].
• 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 [15].
• Interindividual variability of chlorzoxazone 6-hydroxylation in men and women and its relationship to CYP2E1 genetic polymorphisms [16].
• The application of liquid chromatography tandem mass spectrometry for simultaneous analysis of major human cytochrome P450 activities via a single atmospheric pressure ionization (API) LC/MS/MS method has been hampered by the preferred detection of 6-hydroxychlorzoxazone (HCZ), the metabolite of the CYP2E1 probe, chlorzoxazone, under negative API [17].

Anatomical context of chlorzoxazone

• DTIC N-demethylation in a panel of 10 human liver microsome preparations was correlated with the catalytic activities for CYP1A2 (ethoxyresorufin O-deethylation and caffeine N3-demethylation) in the absence of alpha-naphthoflavone and with the catalytic activities for CYP2E1 (chlorzoxazone 6-hydroxylations) in the presence of alpha-naphthoflavone [18].
• Genetic polymorphisms (Pst I and Rsa I restriction fragment length polymorphisms) in the 5'-flanking region of CYP2E1 deoxyribonucleic acid obtained from peripheral leukocytes were not associated with differences in the disposition of chlorzoxazone [16].
• We demonstrated the presence of the CYP2E1 apoprotein in microsomes of RLECs by immunoblot analyses, together with chlorzoxazone 6-hydroxylation, an activity known to be mainly catalyzed by CYP2E1 [19].
• These are open drugs of the skeletal muscle relaxant chlorzoxazone [20].
• This study was carried out to test the specificity of such a substrate when first experiments conducted by using human hepatocyte cultures showed that the chlorzoxazone 6-hydroxylation activity increased after 3-methylcholanthrene treatment of cells [21].

Associations of chlorzoxazone with other chemical compounds

• These data clearly show that chlormethiazole is an efficient inhibitor of chlorzoxazone metabolism and thus of cytochrome P450 2E1 activity in human beings [22].
• Similarly, chlorzoxazone elimination half-life was prolonged after watercress (53%; p < 0.05) and isoniazid (104%; p < 0.01) administration [23].
• METHODS: Twelve healthy men were given 500 mg oral chlorzoxazone after two daily lipopolysaccharide doses (20 endotoxin units/kg/day) and again after administration of saline solution in this balanced crossover study [14].
• Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1 [24].
• OBJECTIVES: Our objectives were to examine the effects of cigarette smoking on the disposition kinetics of chlorzoxazone and caffeine as probes of cytochrome p450 (CYP) 2E1, CYP1A2, xanthine oxidase, and N-acetyltransferase-2 activity and to test the hypothesis that carbon monoxide inhibits drug metabolism via these pathways [25].

Gene context of chlorzoxazone

• Concomitant administration of grapefruit juice (known to be an inhibitor of CYP3A4) with chlorzoxazone did not significantly modify the CHZ metabolic ratio: 0.29 +/- 0.1 versus 0.31 +/- 0.1, for nine control individuals without and with grapefruit juice, respectively [26].
• CYP1A2, 2C8, 2C9, 2C18, 2D6, 3A4 and 3A5 did not appear to be significantly involved in chlorzoxazone metabolism, whereas the participation of CYP1A1 could not be excluded [27].
• Other P450 selective inhibitors did not decrease GBR12909 biotransformation more than 29% in either human liver microsomes or hepatocytes with the exception of chlorzoxazone (CYP2E1), which inhibited GBR12909 biotransformation by 71.4 +/- 18.5% in primary human hepatocytes [28].
• The liver microsomal SOH activity showed significant correlations with tolbutamide hydroxylation (r = 0.569) and chlorzoxazone hydroxylation (r = 0.770) activities, which were the model reactions catalyzed by CYP2C9 and CYP2E1, respectively [29].
• An interaction between the cytochrome P450 probe substrates chlorzoxazone (CYP2E1) and midazolam (CYP3A) [30].

Analytical, diagnostic and therapeutic context of chlorzoxazone

• At postoperative week 6 and year 1, the median body mass index (BMI) of subjects who underwent gastroplasty decreased by 11% and 33%, total oral CLZ clearance declined by 16% (P <.01) and 46% (P <.05), and Cl(u)/F decreased by 18% (P <.05) and 35% (P =.16), respectively [31].
• Chlorzoxazone and the 6-hydroxy metabolite were measured by high-performance liquid chromatography [15].
• METHODS: The plasma concentration-time profiles of chlorzoxazone and its 6-hydroxy metabolite were determined after oral administration of parent drug (250 mg) [3].
• RESULTS: The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean +/- SD, 6.4 +/- 5.1) was significantly higher than that after 1 month after surgery (2.1 +/- 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 +/- 0.5) [32].
• This results from hypothermia-induced decreases in the CYP2E1 enzyme affinity for the substrate chlorzoxazone [33].

References