Influence of diosmin pretreatment on the pharmacokinetics of chlorzoxazone in healthy male volunteers

• Published in: Drug metabolism and drug interactions Vol. 23; no. 3-4; p. 311
• Main Authors: Rajnarayana, K, Venkatesham, A, Nagulu, M, Srinivas, M, Krishna, D R
• Format: Journal Article
• Language: English
• Published: Germany 2008
• Subjects: Adult; Chlorzoxazone - blood; Chlorzoxazone - pharmacokinetics; Chlorzoxazone - urine; Chromatography, High Pressure Liquid - methods; Cytochrome P-450 CYP2E1 - physiology; Cytochrome P-450 CYP2E1 Inhibitors; Diosmin - pharmacology; Drug Interactions; Enzyme Inhibitors - pharmacology; Humans; Male; Muscle Relaxants, Central - blood; Muscle Relaxants, Central - pharmacokinetics; Muscle Relaxants, Central - urine; Young Adult
• ISSN: 0792-5077
• DOI: 10.1515/dmdi.2008.23.3-4.311

Chlorzoxazone, a centrally acting muscle relaxant, is a probe for cytochrome P450 2E1 (CYP2E1). The first part of the study consisted of oral administration of 250 mg of chlorzoxazone (Paraflex 250 tablet) alone to 12 healthy male volunteers. Blood samples were collected from the antecubital vein at intervals of 0, 0.5, 1, 2, 3, 4, 5, 6, 7, and 8 hours and urine voided during 0-4 and 4-8 hours was collected after the administration of chlorzoxazone. The second part of the study was conducted after a wash-out period of 7 days; 500 mg of diosmin (Venex 500) was administered daily for 9 days. On day 10, 250 mg of chlorzoxazone was administered. Blood and urine samples were obtained as mentioned above. Serum levels of chlorzoxazone were determined by HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program RAMKIN. Diosmin pretreatment significantly enhanced AUC, C(max) and t1/2 with a concomitant reduction in CL/f. The urinary excretion of 6-hydroxychlorzoxazone was decreased and unchanged chlorzoxazone was increased over 8 hours. Urinary metabolic ratios of 6-hydroxychlorazoxazone and chlorazoxazone were increased. After pretreatment with diosmin, overall excretion (0-8 h) of 6-hydroxychlorazoxazone and chlorazoxazone were decreased. Diosmin might have inhibited the microsomal CYP2E1-mediated hydroxylation of chlorazoxazone.