Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID). It undergoes extensive Phase I and Phase II metabolism and in vitro it is a specific CYP2C9 substrate. The first part of the study consisted of oral administration of 100 mg of diclofenac sodium (Voveran100) 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. The second part of the study was conducted after a washout period of 7 days. Treatment with 500 mg p.o. of diosmin (Venex 500) was given daily for 9 days. On day 10, 100 mg of diclofenac sodium (Voveran 100) was administered. Blood samples were obtained as mentioned earlier and pharmacokinetic parameters of diclofenac before and after pretreatment with diosmin analyzed by HPLC. Diosmin pretreatment significantly enhanced AUC, C(max) and t1/2 with a concomitant reduction in CL/f. Diosmin might have inhibited the microsomal CYP2C9 mediated oxidation of diclofenac sodium.

No abstract

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.

No abstract

Flavonoids form a large class of phenolic substances widely distributed in nature and exhibit several biological effects. P-glycoprotein is part of a large family of efflux transporters found in the gut, gonads and other organs. Male albino rats were used for this study. The whole small intestine was flushed with 50 ml of ice-cold saline after sacrificing the animal with an overdose of pentobarbital. The small intestine was isolated and divided into duodenum, jejunum and ileum. Each segment was everted, a 5-cm long sac was prepared, 1 ml of nitrendipine solution was introduced into the everted sac (serosal side), and both ends of the sac were ligated tightly. The sac containing nitrendipine solution was immersed in 30 ml of Dulbecco's phosphate buffer solution (D-PBS) containing 25 mM glucose and the same concentration of different bioflavonoids, viz., diosmin, quercetin, chrysin, methyl hesperidin and gossypin, was introduced into the mucosal side. Transport of nitrendipine from serosal to mucosal surfaces across the intestine was determined by collecting samples from the mucosal medium periodically at different intervals: 0, 10, 20, 30, 60, 90 and 120 minutes. The samples were analyzed by HPLC. Diosmin and quercetin decreased the transport rate of nitrendipine to nearly the same extent in all regions. Chrysin and gossypin decreased the transport rate of nitrendipine to a greater extent in the ileum than in the duodenum and jejunum. Methyl hesperidin caused inhibition of nitrendipine transport in the ileum and jejunum, but not in the duodenum. All bioflavonoids, i.e., quercetin, diosmin, methyl hesperidin, gossypin and chrysin, decreased the transport of nitrendipine, a P-gp substrate in the rat intestine. The highest expression of P-gp was found in the ileum followed by the jejunum and duodenum.