Solanidine Metabolites as Diet-Derived Biomarkers of CYP2D6-Mediated Tamoxifen Metabolism in Breast Cancer Patients.

Tamoxifen is an important antiestrogen for the treatment of hormone receptor-positive breast cancer and undergoes bioactivation by CYP2D6 to its active metabolite endoxifen. Genetic variation in CYP2D6 has been linked to endoxifen levels during tamoxifen therapy. Recent studies have suggested solanidine, a glycoalkaloid phytochemical in potatoes, undergoes CYP2D6-mediated metabolism to 4-OH-solanidine (m/z 414) and 3,4-seco-solanidine-3,4-dioic acid (SSDA; m/z 444). Using a retrospective cohort of 1,032 breast cancer patients on tamoxifen therapy, we examined the association of solanidine metabolites with CYP2D6 activity and its correlation with tamoxifen metabolism. Solanidine, 4-OH-solanidine, or SSDA was detected in 99.7% (N = 1,029) of plasma samples. Decreased solanidine metabolite ratios were found in CYP2D6 intermediate and poor metabolizers (P < 0.0001). Patients on CYP2D6 strong inhibitors had a 77.6% and 94.2% decrease in 4-OH-solandine/solanidine (P < 0.0001) and SSDA/solanidine (P < 0.0001), respectively. The ratio of endoxifen to tamoxifen was highly correlated with both 4-OH-solandine/solanidine (ρ = 0.3207, P < 0.0001) and SSDA/solanidine (ρ = 0.5022, P < 0.0001) ratios. Logistic regression modeling was used to determine that 4-OH-solanidine/solanidine and SSDA/solanidine ratios below 2.1 and 0.8, respectively, predicted endoxifen concentrations of <16 nM. In conclusion, solanidine, 4-OH-solanidine, and SSDA are diet-derived biomarkers of CYP2D6 activity. Moreover, in patients on tamoxifen therapy, 4-OH-solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6-interacting medications. Accordingly, 4-OH-solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen.

Impact of organic anion transporting polypeptide, P-glycoprotein, and breast cancer resistance protein transporters on observed tamoxifen and endoxifen concentration and adverse effects.

OBJECTIVE: Drug transporters are important determinants of drug disposition and response. Tamoxifen is an antiestrogen for breast cancer therapy known for adverse drug reactions (ADRs). In this study, the involvement of OATP transporters in tamoxifen and endoxifen transport was studied in vitro while the impact of single nucleotide variation (SNV) in OATP and efflux transporters P-glycoprotein ( ABCB1 ) and Breast Cancer Resistance Protein ( ABCG2 ) on ADRs during tamoxifen therapy were assessed. METHODS: Patients receiving tamoxifen for breast cancer, who were CYP2D6 normal metabolizers were enrolled ( n = 296). Patients completed a survey that captured ADRs and a blood sample was collected. Tamoxifen and endoxifen plasma concentration were measured, while DNA was genotyped for SNVs in ABCB1, ABCG2, SLCO1A2, SLCO1B1 , and SLCO2B1 . HEK293T cells were used to determine the extent of OATP-mediated transport of tamoxifen and endoxifen. RESULTS: Common SNVs of ABCB1, ABCG2, SLCO1A2 , and SLCO1B1 were not associated with tamoxifen or endoxifen concentration. However, tamoxifen concentration was significantly higher in carriers of SLCO2B1 c.935G>A (129.8 ng/mL) compared to wildtype (114.9 ng/mL; P = 0.036). Interestingly, subjects who carried SLCO1A2 c.38A>G reported significantly less dizziness ( P = 0.016). In-vitro analysis demonstrated increased cellular accumulation of tamoxifen in cells overexpressing OATP1A2 and 1B1, but endoxifen uptake was not effected in OATP overexpressing cells. CONCLUSIONS: We showed that OATP1A2 , a transporter known to be expressed at the blood-brain barrier, is capable of tamoxifen transport. Additionally, OATP1A2 c.38A>G was associated with reduced ADRs. Taken together, our findings suggest genetic variation in OATP transporters may be an important predictor of tamoxifen ADRs.

Impact of pretreatment dihydropyrimidine dehydrogenase genotype-guided fluoropyrimidine dosing on chemotherapy associated adverse events.

Consensus guidelines exist for genotype-guided fluoropyrimidine dosing based on variation in the gene dihydropyrimidine dehydrogenase (DPYD). However, these guidelines have not been widely implemented in North America and most studies of pretreatment DPYD screening have been conducted in Europe. Given regional differences in treatment practices and rates of adverse events (AEs), we investigated the impact of pretreatment DPYD genotyping on AEs in a Canadian context. Patients referred for DPYD genotyping prior to fluoropyrimidine treatment were enrolled from December 2013 through November 2019 and followed until completion of fluoropyrimidine treatment. Patients were genotyped for DPYD c.1905+1G>A, c.2846A>T, c.1679T>G, and c.1236G>A. Genotype-guided dosing recommendations were informed by Clinical Pharmacogenetics Implementation Consortium guidelines. The primary outcome was the proportion of patients who experienced a severe fluoropyrimidine-related AE (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Secondary outcomes included early severe AEs, severe AEs by toxicity category, discontinuation of fluoropyrimidine treatment due to AEs, and fluoropyrimidine-related death. Among 1394 patients, mean (SD) age was 64 (12) years, 764 (54.8%) were men, and 47 (3.4%) were DPYD variant carriers treated with dose reduction. Eleven variant carriers (23%) and 418 (31.0%) noncarriers experienced a severe fluoropyrimidine-related AE (p = 0.265). Six carriers (15%) and 284 noncarriers (21.1%) experienced early severe fluoropyrimidine-related AEs (p = 0.167). DPYD variant carriers treated with genotype-guided dosing did not experience an increased risk for severe AEs. Our data support a role for DPYD genotyping in the use of fluoropyrimidines in North America.

Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care.

Factor Xa-inhibitor apixaban is an oral anticoagulant prescribed in atrial fibrillation (AF) for stroke prevention. Its pharmacokinetic profile is known to be affected by cytochrome P450 (CYP)3A metabolism, while it is also a substrate of the efflux transporters ATP-binding cassette (ABC)B1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein, BCRP). In this study, we assessed the impact of interacting medication and pharmacogenetic variation to better explain apixaban concentration differences among 358 Caucasian AF patients. Genotyping (ABCG2, ABCB1, CYP3A4*22, CYP3A5*3) was performed by TaqMan assays, and apixaban quantified by mass spectrometry. The typical patient was on average 77.2 years old, 85.5 kg, and had a serum creatinine of 103.1 µmol/L. Concomitant amiodarone, an antiarrhythmic agent and moderate CYP3A/ABCB1 inhibitor, the impaired-function variant ABCG2 c.421C > A, and sex predicted higher apixaban concentrations when controlling for age, weight and serum creatinine (multivariate regression; R2 = 0.34). Our findings suggest that amiodarone and ABCG2 genotype contribute to interpatient apixaban variability beyond known clinical factors.

Prótesis Parcial Removible con Extensión Distal y Apoyo sobre Implantes, Comportamiento y Consideraciones Clínicas / Removable Partial Denture with Distal Extension and Implant Support, Behavior and Clinical Consideration

La rehabilitación de los extremos libres, en mandíbula uni o bilaterales, suponen un gran reto para el odontólogo, siendo un problema a resolver en la práctica clínica habitual. Tales casos suelen ser resueltos mediante prótesis parcial removible, las cuales deben soportar fuerzas horizontales y de torsión, con efectos adversos durante la función, al producir fuerzas terminales de torque contra pilares y tejidos blandos principalmente por la diferente resiliencia de estas estructuras afectando así la retención, estabilidad y el soporte de la prótesis dental. En el último tiempo se han reportado prótesis parcial removible mandibular en combinación con implante en extremo libre distal como una alternativa a las tradicionales prótesis parcial removible mucodentosoportada y a las prótesis fijas implantosoportadas para el manejo de la desdentición parcial en extremo libre; sin embargo, los reportes publicados en la literatura sobre esta alternativa es limitada respecto a la funcionalidad y el pronóstico. Este artículo presenta una revisión sistematizada de la literatura cuyo objetivo fue identificar y sintetizar la mejor evidencia disponible respecto a las consideraciones y comportamiento clínico de esta modalidad de tratamiento en desdentados de la clase I y II de Kennedy mandibular.

The rehabilitation of free ends in a unilateral or bilateral jaw represents a major challenge for the dentist, and is a problem to solve in the daily clinical practice. These cases are usually resolved by removable partial dentures, which should be able to withstand horizontal forces. Torque adverse effect can occur during functioning, because of torque forces terminals against pillars and soft tissue mainly caused by the different resilience of these structures, therefore affecting retention, stability and support of the dental prosthesis. In recent times it has been reported that mandibular removable partial dentures in combination with distal free end implants can be a viable alternative to traditional removable partial dentures and implant-supported fixed partial dentures for treatment of partial toothless free end, however literature regarding functionality and prognosis of this alternative is limited. This paper presents a systematic literature review aimed to identify and synthesize the best available evidence regarding the considerations and clinical behavior of this treatment modality in edentulous Class I and II of the edentulous Kennedy mandibular.

Prevalencia y severidad de fluorosis dental y su asociación con historia de caries en escolares que consumen agua potable fluorurada en temuco, Chile / Prevalence and severity of dental fluorosis and its association with history of dental caries in schoolchildren consuming fluoridated drinking water in temuco, Chile

La fluoruración del agua potable comenzó a implementarse en Chile en la década de 1950 para prevenir el principal problema de salud oral en la población, la caries dental. Se ha aplicado sistemáticamente en el país, y en Temuco desde el año 2004. Sin embargo, la ingesta de fluoruros en periodos críticos del desarrollo dentario de manera excesiva produce fluorosis dental. El objetivo de este estudio fue determinar la prevalencia y severidad de la fluorosis dental en escolares de segundo básico que consumen agua potable fluorurada en la ciudad de Temuco, Chile y asociarla con la historia de caries. Se realizó un estudio epidemiológico descriptivo y explicativo con un muestreo aleatorio estratificado de la población escolar de 7 años que cursaba segundo básico durante el año 2012 en colegios particulares, subvencionados y municipales de Temuco. Sobre una muestra de 317 niños, se determinó el índice Dean y la historia de caries. La prevalencia de fluorosis dental fue 53,31 por ciento (169 niños), y la severidad fue de tipo cuestionable, muy leve y leve en el 31,36 por ciento, 42,6 por ciento y 22,4 por ciento de los casos, respectivamente. El 3,5 por ciento fue moderado. No se observó asociación significativa entre fluorosis e historia de caries. En Temuco, la prevalencia de fluorosis dental en niños de 7 años es alta, con una severidad de tipo cuestionable, muy leve y leve en más del 50 por ciento de los casos. Luego de 8 años de implementar la fluoruración del agua potable, hubo una disminución del daño acumulado por caries, pero la fluorosis dental aumentó en la población.

Fluoridation of drinking water, began to be implemented in 1950's in Chile to prevent the main problem of oral health in the population, dental caries. It has been consistently applied in the country and Temuco city since 2004. However, intake of fluorides in critical periods of tooth development excessively produces dental fluorosis. The aim was to determine the prevalence and severity of dental fluorosis in elementary schoolchildren consuming fluoridated drinking water in the city of Temuco, Chile and its association with the history of dental caries. A descriptive and explanatory epidemiological study with a stratified random sample of 7-years schoolchildren of private, subsidized and municipal elementary schools in Temuco city was performed. On a sample of 317 children, Dean's index and history of caries was determined. The prevalence of dental fluorosis was 53.31 percent (169 children), and severity rate was questionable, very mild and mild in 31.36 percent, 42.6 percent and 22.4 percent of cases, respectively. In 3.5 percent was moderate. No significant association between fluorosis and history of dental caries was observed. In Temuco, the prevalence of dental fluorosis in 7-years children is high, with severity of questionable, very mild and mild type in 50 percent of cases. After 8 years of implementing the fluoridation of drinking water, there was a decrease of dental caries damage but increased dental fluorosis in the population.