Bioavailability of Diclofenac Sodium After Pretreatment With Diosmin in Healthy Volunteers

Abstract

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.

Inhibition of Cytochrome P450 2C8-mediated Drug Metabolism by the Flavonoid Diosmetin

“…10®15¥ For example, Rajnarayana et al showed that oral treatment of healthy volunteers with diosmin increases significantly the bioavailability of metronidazole, 12¥ diclofenac 14¥ and chlorzoxazone, 15¥ and hypothesized that diosmin-induced inhibition of the CYP enzymes catalyzing the biotransformation of these drugs was responsible for the observed pharmacokinetic interactions. We have recently demonstrated that diosmetin, the absorbable aglycone of diosmin, 16¥ to which orally administered diosmin is converted by rhamnosidases of Enterobacteriaceae, 17¥ is a potent in vitro inhibitor of human CYP3A4/5 18¥ and CYP2C9,19¥ the CYP forms responsible for the metabolism of metronidazole and diclofenac, respectively, 12,14¥ thereby confirming the hypothesis of Rajnarayana et al 12,14¥ Since CYP2C9 shares more than 80% amino acid sequence identity with CYP2C8, 20¥ a CYP form expressed at relatively high levels ¤6®7% of total CYP content¥ in human liver 21¥ and which plays a major role in the metabolism of several therapeutically important drugs, 22¥ the main aim of the present study was to assess whether diosmetin is also an effective inhibitor of human CYP2C8. Because in some pharmaceutical preparations the flavone diosmin is associated with the flavanone hesperidin, which is also likely to be hydrolyzed by intestinal microflora to its aglycone hesperetin, 17¥ a further aim of our study was to test the effect of hesperetin on CYP2C8 activity.…”

Effect of Resveratrol Treatment on the Pharmacokinetics of Diclofenac in Healthy Human Volunteers

“…We have found that, our results are consistent with a human volunteers study reported by Chow et al (), in which CYP2C9 activity of losartan was decreased after administrating 1 g of RSV per day for 4 weeks. In addition, our results are comparable to a human volunteer study reported by Rajnarayana et al () where an increased C max , AUC and T 1/2 with reduced CL/F were found for DIC after administrating 500 mg of diosmin per day for 9 days and the observed effects are most likely the result of inhibition of activity of CYP2C9 enzyme. In addition, an in vitro study has reported that resvertarol‐3‐sulfate, metabolite of RSV, inhibited the activity of CYP2C9 enzyme (Detampel et al, ).…”

Evaluation of the effect of quercetin treatment on CYP2C9 enzyme activity of diclofenac in healthy human volunteers

“…On the basis of the results of a previous pharmacokinetic study (Rajnarayana et al, ), we calculated that 12 healthy volunteers would be required to demonstrate a 20% difference in maximum plasma concentration (C max) and area under the plasma concentration‐time curve (AUC 0‐∞ ) of DIC between control and quercetin treatment phases at a 5% significance level with 80% statistical power. Therefore, 12 healthy male volunteers (age, 26–32; weight, 60–74 kg; and body mass index, 18.30–26.25 kg/m 2 ) were included in the present study.…”

“…As a CYP2C9 substrate, DIC has the potential to interact with various inhibitors and inducers of CYP2C9 enzyme. Several drugs (Hynninen et al, ; Kovarik et al, ; Pedrazzoli Júnior et al, ) and herbal constituents (Bedada, Boga, & Kotakonda, ; Bedada, Yellu, & Neerati, ; Rajnarayana et al, ) altered the pharmacokinetics of DIC due to modulation of CYP2C9 enzyme in humans.…”