title: Modulation of CYP2D6 and CYP3A4 metabolic activities by Ferula asafetida resin.
abstract: 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.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Fahad I
authors.initials: FI
authors.lastname: Al-Jenoobi
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Areej A
authors.initials: AA
authors.lastname: Al-Thukair
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mohd Aftab
authors.initials: MA
authors.lastname: Alam
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Fawkeya A
authors.initials: FA
authors.lastname: Abbas
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdullah M
authors.initials: AM
authors.lastname: Al-Mohizea
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy and Biomarkers Research Program, College of Science, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Alkharfy
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Saleh A
authors.initials: SA
authors.lastname: Al-Suwayeh
keywords: Asafetida; CYP2D6; CYP3A4; Dextromethorphan; Interaction; Metabolism; Microsomes