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 relationsh...

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Published in:	Drug metabolism and pharmacokinetics Vol. 31; no. 5; pp. 349 - 355
Main Authors:	Sánchez-Martín, Almudena, Cabrera Figueroa, Salvador, Cruz, Raquel, Porras-Hurtado, Liliana, Calvo-Boyero, Fernando, Rasool, Mahmood, Bustos, Carmen, Cordero, Miguel, Fuertes, Aurelio, Iglesias, Alicia, Luna, Guillermo, Valverde, Ma Paz, Domínguez-Gil Hurlé, Alfonso, Carracedo, Angel
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-10-2016
Subjects:	Adolescent Adult Aged Anti-HIV Agents - pharmacokinetics Anti-HIV Agents - therapeutic use Benzoxazines - pharmacokinetics Benzoxazines - therapeutic use CYP2B6 Cytochrome P-450 CYP2B6 - genetics DRD3 Efavirenz pharmacokinetics Female Genetic factors Gene–gene interactions Genotype HIV Infections - drug therapy HIV Infections - genetics Humans Male Middle Aged MRP4 Multidrug Resistance-Associated Proteins - genetics Polymorphism, Single Nucleotide - genetics Receptors, Dopamine D3 - genetics Young Adult Efavirenz pharmacokinetics Gene–gene interactions CYP2B6 Genetic factors MRP4 DRD3
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1347-4367 1880-0920
DOI:	10.1016/j.dmpk.2016.06.001