• Guillermo Gervasini, Carlos Jara, Clara Olier, Nuria Romero, Ruth Martínez, and Juan Antonio Carrillo.
• Department of Medical and Surgical Therapeutics, Division of Clinical Pharmacology, Medical School, University of Extremadura, Alcorcón, Madrid, Spain.
• Br J Clin Pharmacol. 2017 Mar 1; 83 (3): 562-571.

AimsAnastrozole, an aromatase inhibitor widely used in breast cancer, has recently been indicated to be a P-glycoprotein (ABCB1) substrate. We have aimed to determine whether ABCB1 single-nucleotide polymorphisms (SNPs) can affect anastrozole plasma concentrations in these patients. In addition, we assessed the impact of SNPs in CYP19A1 and TCL1A on the development of arthralgia and cancer recurrence in our series.MethodsThis study included 110 postmenopausal women with hormone receptor-positive breast cancer. Anastrozole plasma levels were determined by a liquid chromatography-electrospray ionization-quadrupole-time-of-flight mass spectrometry system. Patients were genotyped for SNPs in the ABCB1, TCL1A and CYP19A1 genes to search for associations with pharmacokinetic and pharmacodynamics parameters using logistic regression models.ResultsAnastrozole concentrations showed an almost nine-fold interindividual variability (mean 26.95 ± 11.91 ng ml-1 ). The ABCB1 2677-TT genotype was associated with higher plasma levels (32.22 ± 12.82 vs. 25.86 ± 11.56 ng ml-1 for GG/GT subjects; 95% confidence interval: -12.3 to -0.40), whilst the 3435-TT genotype showed a protective effect on the risk of arthralgia (odds ratio = 0.32 [0.11-0.89]; P = 0.029). The CYP19A1 rs1008805 GG genotype was strongly and inversely associated with arthralgia (odds ratio = 0.24 [0.09-0.65], P = 0.004); however, SNPs near the TCL1A gene were not linked to this adverse effect. None of the patients who had cancer recurrence harboured the CYP19A1 rs727479 AA genotype, which, in contrast, was present in 38% of patients who did not relapse (P for trend = 0.031).ConclusionOur findings indicate that variability in anastrozole plasma levels may be attributable to the status of the ABCB1 gene locus. Furthermore, genetic variants in CYP19A1 were associated with arthralgia and cancer recurrence in our patients.© 2016 The British Pharmacological Society.

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