Effects of genetic polymorphisms of drug metabolizing enzymes and co-medications on tamoxifen metabolism in black South African women with breast cancer.

Clinical outcomes of tamoxifen treatment show wide inter-individual variability. Co-medications and genetic polymorphisms of enzymes involved in tamoxifen metabolism contribute to this variability. Drug-drug and drug-gene interactions have seldom been studied in African black populations. We evaluated the effects of commonly co-administered medicines on tamoxifen pharmacokinetics in a cohort of 229 South African black female hormone-receptor positive breast cancer patients. We also investigated the pharmacokinetic effects of genetic polymorphism in enzymes involved in tamoxifen metabolism including the variants CYP2D6*17 and *29 which have been mainly reported in people of African descent. Tamoxifen (TAM) and its major metabolites, N-desmethyltamoxifen (NDM), 4-OH-tamoxifen (4-OHTAM), and endoxifen (ENDO), were quantified in plasma using the liquid chromatography-mass spectrometry (LC/MS/MS). The GenoPharm® open array was used to genotype CYP2D6, CYP3A5, CYP3A4, CYP2B6, CYP2C9, and CYP2C19. Results showed that CYP2D6 diplotype and CYP2D6 phenotype significantly affected endoxifen concentration (p<0.001 and p<0.001). CYP2D6*17 and CYP2D6*29 significantly reduced the metabolism of NDM to ENDO. Antiretroviral therapy (ART) had a significant effect on NDM levels and the TAM/NDM and NDM/ENDO Metabolic Ratios (MRs) but did not result in significant effects on ENDO levels. In conclusion, CYP2D6 polymorphisms affected endoxifen concentration and the variants CYP2D6*17 and CYP2D6*29 significantly contributed to low exposure levels of endoxifen. This study also suggests a low risk of drug-drug interaction in breast cancer patients on tamoxifen.