Study of cytochrome P450 (CYP2C9) polymorphyms for pharmacogenetic tests

• Grant number: 18/02556-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2018
• End date: March 31, 2021
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Adriana Maria Calvo
• Grantee: Bruna Bolani
• Host Institution: Faculdade de Odontologia de Bauru (FOB). Universidade de São Paulo (USP). Bauru , SP, Brazil
• Associated research grant: 17/12725-0 - Model of pharmakinetics/pharmacodynamics (PK/PD) on the influence of P450 genetic polymorphism (CYP2C9) of non-steroidal anti-inflammatory drugs and main metabolics from saliva samples through LCMS/MS and its role on prescription personalization, AP.JP

Abstract

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with serious adverse drug reactions, mainly in the gastrointestinal tract and renal and cardiovascular system. Pharmacogenetics is the study of the molecular basis of genetic factors that can influence the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug, changing its toxicity profile and efficacy, and clinical studies of the control of inflammatory signs are still scarce in the literature. Cytochrome P450 (CYP) 2C9 is about 20% of all human hepatic cytochromes and metabolizes approximately 15% of the drugs available on the market. The most frequent and most relevant allelic variants for this project are: CYP2C9 * 2 (430C> T, rs1799853) and CYP2C9 * 3 (1075A> C, rs1057910), both resulting in a decrease in CYP2C9 activity. The frequency of these alleles shows large inter-ethnic differences, which for the Brazilian population may represent an obstacle in the characterization of frequency in general. The relative contribution of CYP2C9 to NSAID metabolism differs to a large extent between different drugs, but CYP2C9 plays an important role in the metabolism of most NSAIDs. In summary, in all pharmacogenetic studies, almost all NSAIDs for which PK data are available in relation to CYP2C9 polymorphisms show a decrease in in vitro or in vivo elimination and, therefore, a possible accumulation and increase of toxicity mainly in CYP2C9 * 3 / * 3 subjects, but also in heterozygous carriers of CYP2C9 (CYP2C9 * 2, CYP2C9 * 3, CYP2C9 * 8 and CYP2C9 * 13). The aim of this IC bag is to screen and genotype as many volunteers as necessary to find 15 non-mutated individuals and 15 mutated individuals for CYP2C9, who will compose the main research sample, in an attempt to confirm the hypothesis of the main project of the Youth Researcher who subjects with the polymorphic genotype in the CYP2C9 gene have slower metabolism and less effective action of the NSAIDs in question in the control of inflammatory signs. In addition, these people should be affected by more adverse effects compared to those with wild genotype.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BRUNA BOLANI; GABRIELA MORAES OLIVEIRA; THIAGO JOSÉ DIONÍSIO; FLAVIO AUGUSTO CARDOSO FARIA; MARIA HELENA RAPOSO FERNANDES; CARLOS FERREIRA SANTOS; ADRIANA MARIA CALVO. Pharmacogenetic and Pharmacokinetic Assays from Saliva Samples Can Guarantee Personalized Drug Prescription. Brazilian Dental Journal, v. 32, n. 1, p. 3-8, 2021-04-02. (18/02556-0, 17/12725-0, 09/17851-8)