AUTHOR=Mejía-Abril Gina , Zubiaur Pablo , Navares-Gómez Marcos , Villapalos-García Gonzalo , Román Manuel , Ochoa Dolores , Abad-Santos Francisco 

TITLE=Dexketoprofen Pharmacokinetics is not Significantly Altered by Genetic Polymorphism

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.660639

DOI=10.3389/fphar.2021.660639

ISSN=1663-9812

ABSTRACT=<p>Dexketoprofen is the (S)-(+)-enantiomer of racemic ketoprofen, a nonsteroidal anti-inflammatory drug used for the management of different types of pain. To the best of our knowledge, no article was published to date on dexketoprofen pharmacogenetics. Thence, in this work, we aimed to explore the influence of sex, race and several single nucleotide polymorphisms (SNPs) in genes encoding metabolizing enzymes (e.g. <italic>CYP</italic> or <italic>UGT</italic>) or transporters (e.g., <italic>ABC or SLC</italic>) in the pharmacokinetics and safety of dexketoprofen to explore whether dosing adjustments based on genetic polymorphism would be beneficial for its prescription. For this regard, 85 healthy volunteers enrolled in three bioequivalence clinical trials were genotyped for 46 SNPs in 14 genes. Women showed lower AUC adjusted by dose/weight (AUC/DW) and higher Vd/F and Cl/F than men (<italic>p</italic> &lt; 0.05 in univariate and multivariate analysis). <italic>CYP1A2*</italic>1B allele, <italic>CYP2B6</italic> IM/PM and <italic>CYP2D6</italic> IM/PM phenotypes were related to drug accumulation (AUC/DW or Cmax/DW) compared to the <italic>CYP1A2</italic>*1 allele, <italic>CYP2B6</italic> NM/RM and <italic>CYP2D6</italic> NM/UM phenotypes (<italic>p</italic> &lt; 0.05 in the univariate analysis). <italic>ABCB1</italic> C1236TT, C3435TT and G2677A/TA/T alleles were related to lower Cmax/DW compared to C, C, and G alleles (<italic>p</italic> &lt; 0.05 in univariate and multivariate analysis). <italic>ABCB1</italic> C1236TT allele was also related to lower AUC/DW (<italic>p</italic> &lt; 0.05 in multivariate analysis). The remaining studied transporter genes (<italic>ABCC2</italic>, <italic>SLC22A1</italic>, and <italic>SLCO1B1</italic>) and metabolizing enzyme genes (<italic>CYP3A5</italic>, <italic>CYP2C19</italic>, <italic>CYP2C9</italic>, <italic>CYP2C8</italic>, <italic>CYP3A4</italic>, <italic>CYP2A6</italic>, and <italic>UGT1A1</italic>) were unrelated to dexketoprofen pharmacokinetic variability. We conclude that dexketoprofen pharmacokinetics can be influenced by several polymorphisms, although there is not a clear pharmacogenetic predictor that would justify individualization of therapy based on its genotyping. Further studies should be conducted to confirm the role of SNPs in <italic>CYP2B6</italic>, <italic>CYP2D6</italic>, <italic>CYP1A2</italic> and <italic>ABCB1</italic> on the pharmacokinetic variability of dexketoprofen. Current evidence on dexketoprofen pharmacogenetics does not justify its inclusion in pharmacogenetic guidelines.</p>