Gene-gene interactions between DRD3, MRP4 and CYP2B6 polymorphisms and its influence on the pharmacokinetic parameters of efavirenz in HIV infected patients.
Genetic factors have a significant impact on the PK variability of EFV, much higher than other non-genetic factors, such as demography. In this work we have performed a comprehensive PG analysis of genes encoding the major metabolizing enzymes and transporters of EFV, establishing a clear relationship between the PK parameters and genetic factors, which explain 50% of the variability in EFV PK parameters. The most relevant associations for metabolizing enzymes were found in CYP2B6 (rs3745274), in agreement with previous studies. The influence of transporters on the kinetics of EFV was also proved with significant correlations between the PK parameters of EFV and MRP4 (rs1751034, rs2274407). Analysis of gene-gene interactions with CYP2B6 was particularly useful to reinforce the role of MRP4 and to reveal unknown associations, such as that of DRD3. However, the role of DRD3 cannot be a direct effect but an indirect one due to physical proximity of NAT and the DRD3 locus in the genome.
Pharmacy Service, University Hospital of Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain.
Almudena
A
Sánchez-Martín
Pharmacy Service, University Hospital of Salamanca, Paseo San Vicente 58-182, 37007 Salamanca, Spain; Instituto de Farmacia, Facultad de Ciencias, Universidad Austral de Chile, Edificio Emilio Pugín, Avenida Eduardo Morales Miranda, Campus Isla Teja, Valdivia, Región de los Ríos, Chile.
Salvador
S
Cabrera Figueroa
Grupo de Medicina Xenómica, CIBERER, CIMUS, Universidad de Santiago de Compostela, Avenida de Barcelona s/n, 15782 Santiago de Compostela, Spain. Electronic address: raquel.cruz@usc.es.
Raquel
R
Cruz
Grupo de Medicina Xenómica, CIBERER, CIMUS, Universidad de Santiago de Compostela, Avenida de Barcelona s/n, 15782 Santiago de Compostela, Spain; Comfamiliar Risaralda, Avenida Circunvalar Número 3-01, Pereira, Rirasalda, Colombia.
Liliana
L
Porras-Hurtado
Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Salamanca, Campus Miguel de Unamuno, Calle Lic. Méndez Nieto s/n, 37007 Salamanca, Spain.
Fernando
F
Calvo-Boyero
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, 21589 Jeddah, Saudi Arabia.
Mahmood
M
Rasool
Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Salamanca, Campus Miguel de Unamuno, Calle Lic. Méndez Nieto s/n, 37007 Salamanca, Spain.
Alfonso
A
Domínguez-Gil Hurlé
Grupo de Medicina Xenómica, CIBERER, CIMUS, Universidad de Santiago de Compostela, Avenida de Barcelona s/n, 15782 Santiago de Compostela, Spain; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, P.O. Box 80216, 21589 Jeddah, Saudi Arabia; Fundación Medicina Xenómica, SERGAS, Complexo Hospitalario Universitario de Santiago, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain.
Angel
A
Carracedo
D000293:Adolescent; D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048588:Benzoxazines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D055815:Young Adult
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D050637:Receptors, Dopamine D3; C073492:ABCC4 protein, human; C493593:DRD3 protein, human; C585599:CYP2B6 protein, human; C098320:efavirenz
CYP2B6; DRD3; Efavirenz pharmacokinetics; Genetic factors; Gene–gene interactions; MRP4