Diego A C Cusinato1, Edson Z Martinez2, Mônica T C Cintra3, Gabriela C O Filgueira4, Andresa A Berretta5, Vera L Lanchote1, Eduardo B Coelho6. 1. School of Pharmaceutical Sciences of Ribeirão Preto, Department of Clinical Analysis, Toxicology and Food Science, University of São Paulo, Brazil. 2. Ribeirão Preto Medical School, Department of Social Medicine, University of São Paulo Ribeirão Preto, Brazil. 3. General Clinical Research Center, Teaching Hospital Ribeirão Preto, Brazil. 4. Medical School, University of São Paulo Medical School, Department of Obstetrics and Gynecology, University of São Paulo, Brazil. 5. Laboratório de Pesquisa, Desenvolvimento & Inovação, Apis Flora Indl. Coml. Ltda., Ribeirão Preto, SP, Brazil. 6. School of Pharmaceutical Sciences of Ribeirão Preto, Department of Clinical Analysis, Toxicology and Food Science, University of São Paulo, Brazil; Ribeirão Preto Medical School, Department of Internal Medicine, University of São Paulo, Brazil. Electronic address: ebcoelho@fmrp.usp.br.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs. AIM OF THE STUDY: The main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach. MATERIALS AND METHODS: Subtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves. RESULTS: After exposure to EPP-AF®, it was observed decrease in the AUC0-∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80-1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80-1.25. CONCLUSIONS: In conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis.
ETHNOPHARMACOLOGICAL RELEVANCE: Propolis has been employed extensively in many cultures since ancient times as antiseptic, wound healing, anti-pyretic and others due to its biological and pharmacological properties, such as immunomodulatory, antitumor, anti-inflammatory, antioxidant, antibacterial, antiviral, antifungal, antiparasite activities. But despite its broad and traditional use, there is little knowledge about its potential interaction with prescription drugs. AIM OF THE STUDY: The main objective of this work was to study the potential herbal-drug interactions (HDIs) of EPP-AF® using an in vivo assay with a cocktail approach. MATERIALS AND METHODS: Subtherapeutic doses of caffeine, losartan, omeprazole, metoprolol, midazolam and fexofenadine were used. Sixteen healthy adult volunteers were investigated before and after exposure to orally administered 125 mg/8 h (375 mg/day) EPP-AF® for 15 days. Pharmacokinetic parameters were calculated based on plasma concentration versus time (AUC) curves. RESULTS: After exposure to EPP-AF®, it was observed decrease in the AUC0-∞ of fexofenadine, caffeine and losartan of approximately 18% (62.20 × 51.00 h.ng/mL), 8% (1085 × 999 h.ng/mL) and 13% (9.01 × 7.86 h.ng/mL), respectively, with all 90% CIs within the equivalence range of 0.80-1.25. On the other hand, omeprazole and midazolam exhibited an increase in AUC0-∞ of, respectively, approximately 18% (18.90 × 22.30 h.ng/mL) and 14% (1.25 × 1.43 h.ng/mL), with the upper bounds of 90% CIs slightly above 1.25. Changes in pharmacokinetics of metoprolol or its metabolite α-hydroxymetoprolol were not statistically significant and their 90% CIs were within the equivalence range of 0.80-1.25. CONCLUSIONS: In conclusion, our study shows that EPP-AF® does not clinically change CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities, once, despite statistical significant, the magnitude of the changes in AUC values after EPP-AF® were all below 20% and therefore may be considered safe regarding potential interactions involving these enzymes. Besides, to the best of our knowledge this is the first study to assess potential HDIs with propolis.
Authors: Marcelo Augusto Duarte Silveira; David De Jong; Andresa Aparecida Berretta; Erica Batista Dos Santos Galvão; Juliana Caldas Ribeiro; Thiago Cerqueira-Silva; Thais Chaves Amorim; Luis Filipe Miranda Rebelo da Conceição; Marcel Miranda Dantas Gomes; Maurício Brito Teixeira; Sergio Pinto de Souza; Marcele Helena Celestino Alves Dos Santos; Raissa Lanna Araújo San Martin; Márcio de Oliveira Silva; Monique Lírio; Lis Moreno; Julio Cezar Miranda Sampaio; Renata Mendonça; Silviana Salles Ultchak; Fabio Santos Amorim; João Gabriel Rosa Ramos; Paulo Benigno Pena Batista; Suzete Nascimento Farias da Guarda; Ana Verena Almeida Mendes; Rogerio da Hora Passos Journal: Biomed Pharmacother Date: 2021-03-20 Impact factor: 6.529