Analysis of the influence of EPP-AF® on the major CYP isoforms.

• Grant number: 12/18826-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2013
• End date: October 31, 2013
• Field of knowledge: Health Sciences - Pharmacy - Pharmacognosy
• Principal Investigator: Vera Lúcia Lanchote
• Grantee: Diego Alberto Ciscato Cusinato
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Studies using propolis standardized extract (EPP-AF®) showed anti-inflammatory, healing, antimicrobial, antioxidant and antifungal activities and resulted in the approval of a patent request (PI0405483-0). Artepillin C, one of its biomarker, exhibited good oral bioavailability and presented itself as suitable molecule for anti-inflammatory drug development. Therefore to have its use approved as a new drug, clinical trials assessing the safety and efficacy of EPP-AF® are needed. One of the bottlenecks in the national drug development program lies on the assessment of cytochrome P450 (CYP) and transport proteins drug interactions profile. This matter is even more relevant when dealing with natural products which are multi-component compounds that hamper in vitro studies. In this scenario the main goal of this project is to perform a clinical trial to evaluate the influence of EPP-AF® over the major CYP isoforms through an in vivo assay using multiple drug biomarkers (Cooperstown Cocktail) according to the FDA (Food and Drug Administration, 2006) guidance to clinical drug development. This study also intends to obtain data from an in vitro assay regarding EPP-AF® metabolism in collaboration with a University abroad and compare to data obtained in in vivo assays. We expect this comparison will help us to understand the advantages and limitations of using in vitro assays with a compound derived from a natural product regarding the use of in vivo methodologies. This study is an open-label, two-phase non-randomized clinical trial: control and EPP-AF® treatment (125 mg/8h for 15 days). Sixteen healthy volunteers subject to Cooperstown 5+1 Cocktail, midazolam (0.025 mg/Kg intravenous), caffeine (100 mg orally), omeprazole (20 mg orally), metoprolol (100 mg orally) and losartan (25 mg orally) will be investigated. Clearance and metabolic ratio will be calculated to asses CYP1A2, CYP2C19, CYP2D6, CYP3A, XO (xanthine oxidase) and NAT2 activities. Data will be reported as 90% confidence interval about the geometric mean ratio of the observed pharmacokinetic measures with and without the interacting drug and analyzed with the use of non-parametric repeated measures ANOVA and Mann-Whitney or Wilcoxon for safety protocols. The limit of signicance accepted for all statistical analyses are those with p<0.10 (safety, FDA 2012).