Hepatic cytochrome P450 2E1 activity in nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a worldwide phenomenon spanning all the continents. The pathogenesis of NAFLD has not been completely elucidated. One hypothesis is that hepatic cytochrome P450 2E1 (CYP2E1) plays an important role in increasing the lipid peroxidation and oxidative stress in NAFLD. OBJECTIVE: The aim of the present study was to examine hepatic CYP2E1 activity in patients with NAFLD. MATERIAL AND METHOD: Healthy subjects were included. After an overnight fasting, the subjects were orally administered 400 mg chlorzoxazone (CHZ) and serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 hours after dosing. For patients with NAFLD, plasma samples were collected at 0 (predose), 1.5, 2, 2.5 and 3 hours after dosing. Plasma CHZ and 6-hydroxychlorzoxazone (6-OH-CHZ) was assayed by reversed-phase high-performance liquid chromatography (HPLC) with UV detector. Hepatic CYP2E1 activity was calculated by using concentration ratio of 6-OH-CHZ / CHZ. RESULTS: High concentration levels of CHZ and 6-OH-CHZ in healthy subjects were found between 1.5 to 3 hours after the dose. At 1.5 to 3 hours, the concentration ratio of 6-OH-CHZ / CHZ of patients with NAFLD seemed to be more than of healthy subjects. The time point which showed most different was 2.5 hours. (0.40 +/- 0.27 vs. 0.25 +/- 0.12 microg/ml, respectively, p = 0.10). CONCLUSION: Although significant difference of the concentration ratio of 6-OH-CHZ / CHZ between the two groups was not exhibited, the data demonstrated the possibility of the increasing hepatic CYP2E1 activity in NAFLD. The concentration ratio of 6-OH-CHZ / CHZ at the point 2.5 hours may be the best index for measuring hepatic CYP2E1 activity in NAFLD.

A study on the pharmacokinetics of chlorzoxazone in healthy Thai volunteers.

BACKGROUND: Chlorzoxazone (CHZ), a centrally acting skeletal muscle relaxant, is metabolized to 6-hydroxychlorzoxazone (6-OH-CHZ) by CYP2E1. CHZ can be used as an in vivo probe of CYP2E1 activity in patients with liver diseases. Pharmacokinetics of CHZ in Thai subjects should be studied for application to Thai patients. OBJECTIVE: The purpose of the present study was to determine clinical pharmacokinetics of CHZ and 6-OH-CHZ. MATERIAL AND METHOD: Ten healthy Thai volunteers were included. After an overnight fasting, the volunteers were orally administered 400 mg CHZ and serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours after dosing. Plasma CHZ and 6-OH-CHZ were assayed by reversed-phase high-performance liquid chromatography (HPLC) with UV detector. The pharmacokinetic parameters including maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the concentration-time curve (AUC0-8 and AUC0-infinity), elimination half-life (t1/2), elimination rate constant (K(el)), oral clearance (Cl), and volume of distribution (Vd) were determined. RESULTS: CHZ was absorbed into systemic circulation with time to reach maximum concentration (Tmax) of 2.00 +/- 0.82 hrs and maximum concentration (Cmax) of 7.15 +/- 2.09 microg/ml. It was metabolized to 6-OH-CHZ with Tmax of 3.05 +/- 1.17 hrs and Cmax of 1.77 +/- 0.50 microg/ml. The extent of CHZ absorption (area under the concentration-time curve, AUC) was 25.47 +/- 7.11 and 27.52 +/- 8.05 microg x hr/ml for AUC0-8 and AUC0-infinity respectively. The AUC0-8 and AUC0-infinity of 6-OH-CHZ were 7.32 +/- 2.21 and 8.50 +/- 2.78 microg x hr/ml, respectively. The elimination rate constant (K(el)) was 0.48 +/- 0.10 and 0.40 +/- 0.13 hr-1 for CHZ and 6-OH-CHZ, respectively The elimination half-life (t1/2) was 1.49 +/- 0.32 and 1.95 +/- 0.73 hours for CHZ and 6-OH-CHZ, respectively. Oral clearance (Cl) and volume of distribution (Vd) of CHZ was found to be 15.77 +/- 4.81 (L/hr) and 33.13 +/- 9.75 L, respectively. CONCLUSION: An oral dose of 400 mg CHZ was used to probe for the pharmacokinetic characteristics of this drug in Thai volunteers. Those parameters reflected absorption, distribution, and elimination of CHZ in healthy Thai volunteers.