Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A2*2 and SULT1A2*3 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.
Older adults are at increased risk of several cytochrome P450 (CYP) drug interactions that can result in drug toxicity, reduced pharmacological effect, and adverse drug reactions. This study aimed to assess the prevalence of potential CYP interactions referring to the most clinically relevant drugs and exploring the relationship between them and quality of life and physical performance in Spanish octogenarians. Institutionalized and community-dwelling octogenarians (n = 102) treated at three primary care centers, were recruited by a research nurse. Anthropometric measurements, chronic diseases, prescribed drugs, quality of life, physical performance, mobility skills, hand grip strength and cognitive status data were collected. Potential CYP drug-drug interactions (DDIs) were selected referring to the main CYP implicated in their metabolism. The 72.2% of recruited octogenarians presented potentially inappropriate CYP inhibitor-substrate or CYP inductor-substrate combinations. Analyzing the EuroQol Visual Analogue scale (EQ-VAS) results, patients with a potential CYP DDI perceived worse health status than patients without it (p = 0.004). In addition, patients with a potential CYP DDI presented worse exercise capacity, kinesthetic abilities, or mobility than those who didn’t present a potential interaction (p = 0.01, p = 0.047, and p = 0.02, respectively). To investigate and control factors associated with loss of muscle strength and poor quality of life, polypharmacy and DDIs could help institutions in the management of physical frailty.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.