Effect of Trigonella foenum-graecum L. on Metabolic Activity of CYP2D6 and CYP3A4.

BACKGROUND: The present study investigated the effect of fenugreek seeds powder and its alcoholic extract on metabolic activity of drug-metabolizing enzymes CYP2D6 and CYP3A4. MATERIALS AND METHODS: Dextromethorphan (DEX) was used as a probe for measuring metabolic activity, based on its CYP2D6- and CYP3A4-mediated metabolism to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. For the in vitro investigations, DEX (25µM) was incubated with human liver microsomes and NADPH and tested with and without the fenugreek extract. For the in vivo study, phase I, 6 subjects received a single dose of DEX (30 mg); in phase II, after washout period, the fenugreek seeds powder was administered for 1 week and DEX was administered with its last dose. RESULTS: In vitro, fenugreek extract inhibits CYP2D6-mediated O-demethylation of DEX. Higher concentrations (50 and 100µg/ml) of extract inhibit CYP2D6 and CYP3A4 activity. In vivo results indicated that fenugreek does not significantly inhibit CYP2D6 and CYP3A4 metabolic activity. There was no significant change in the levels of DEX metabolites (DOR 12% and 3-MM 9%) excreted in urine and their urine metabolic ratios (P values: 0.257 and 0.333 DEX/DOR and DEX/3-MM, respectively). CONCLUSION: In vitro and in vivo observations suggested that fenugreek may not have substantial effect on the metabolic activity of CYP2D6 and CYP3A4.

Effect of Curcuma longa on CYP2D6- and CYP3A4-mediated metabolism of dextromethorphan in human liver microsomes and healthy human subjects.

Effect of Curcuma longa rhizome powder and its ethanolic extract on CYP2D6 and CYP3A4 metabolic activity was investigated in vitro using human liver microsomes and clinically in healthy human subjects. Dextromethorphan (DEX) was used as common probe for CYP2D6 and CYP3A4 enzymes. Metabolic activity of CYP2D6 and CYP3A4 was evaluated through in vitro study; where microsomes were incubated with NADPH in presence and absence of Curcuma extract. In clinical study phase-I, six healthy human subjects received a single dose (30 mg) of DEX syrup, and in phase-II DEX syrup was administered with Curcuma powder. The enzyme CYP2D6 and CYP3A4 mediated O- and N-demethylation of dextromethorphan into dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. Curcuma extract significantly inhibited the formation of DOR and 3-MM, in a dose-dependent and linear fashion. The 100 µg/ml dose of curcuma extract produced highest inhibition, which was about 70 % for DOR and 80 % for 3-MM. Curcuma significantly increases the urine metabolic ratio of DEX/DOR but the change in DEX/3-MM ratio was statistically insignificant. Present findings suggested that curcuma significantly inhibits the activity of CYP2D6 in in vitro as well as in vivo; which indicates that curcuma has potential to interact with CYP2D6 substrates.

Effect of Garden Cress Seeds Powder and Its Alcoholic Extract on the Metabolic Activity of CYP2D6 and CYP3A4.

The powder and alcoholic extract of dried seeds of garden cress were investigated for their effect on metabolic activity of CYP2D6 and CYP3A4 enzymes. In vitro and clinical studies were conducted on human liver microsomes and healthy human subjects, respectively. Dextromethorphan was used as a common marker for measuring metabolic activity of CYP2D6 and CYP3A4 enzymes. In in vitro studies, microsomes were incubated with NADPH in presence and absence of different concentrations of seeds extract. Clinical investigations were performed in two phases. In phase I, six healthy female volunteers were administered a single dose of dextromethorphan and in phase II volunteers were treated with seeds powder for seven days and dextromethorphan was administered with last dose. The O-demethylated and N-demethylated metabolites of dextromethorphan were measured as dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. Observations suggested that garden cress inhibits the formation of DOR and 3-MM metabolites. This inhibition of metabolite level was attributed to the inhibition of CYP2D6 and CYP3A4 activity. Garden cress decreases the level of DOR and 3-MM in urine and significantly increases the urinary metabolic ratio of DEX/DOR and DEX/3-MM. The findings suggested that garden cress seeds powder and ethanolic extract have the potential to interact with CYP2D6 and CYP3A4 substrates.

Modulation of CYP2D6 and CYP3A4 metabolic activities by Ferula asafetida resin.

Present study investigated the potential effects of Ferula asafetida resin on metabolic activities of human drug metabolizing enzymes: CYP2D6 and CYP3A4. Dextromethorphan (DEX) was used as a marker to assess metabolic activities of these enzymes, based on its CYP2D6 and CYP3A4 mediated metabolism to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. In vitro study was conducted by incubating DEX with human liver microsomes and NADPH in the presence or absence of Asafetida alcoholic extract. For clinical study, healthy human volunteers received a single dose of DEX alone (phase-I) and repeated the same dose after a washout period and four-day Asafetida treatment (phase-II). Asafetida showed a concentration dependent inhibition on DOR formation (in vitro) and a 33% increase in DEX/DOR urinary metabolic ratio in clinical study. For CYP3A4, formation of 3-MM in microsomes was increased at low Asafetida concentrations (10, 25 and 50 µg/ml) but slightly inhibited at the concentration of 100 µg/ml. On the other hand, in vivo observations revealed that Asafetida significantly increased DEX/3-MM urinary metabolic ratio. The findings of this study suggest that Asafetida may have a significant effect on CYP3A4 metabolic activity. Therefore, using Ferula asafetida with CYP3A4 drug substrates should be cautioned especially those with narrow therapeutic index such as cyclosporine, tacrolimus and carbamazepine.