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.


METHODS
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.


CONCLUSIONS
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.
Prompila
Nantaporn
N
Department of Pharmacology, Faculty and Medicine, Chulalongkorn Unversity, Bangkok 10330, Thailand.
Wittayalertpanya
Supeecha
S
Komolmit
Piyawat
P
D000328:Adult; D019540:Area Under Curve; D002753:Chlorzoxazone / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D002845:Chromatography; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D008297:Male; D009125:Muscle Relaxants, Central / Q000097:blood / Q000493:pharmacokinetics*; D013785:Thailand
D009125:Muscle Relaxants, Central; C039289:6-hydroxychlorzoxazone; D002753:Chlorzoxazone