Inter-individual differences in thyroid hormone bioactivity: the effect of genetic variation

Adequate levels of thyroid hormone are essential for normal development and growth, since thyroid hormone plays an important role in virtually all metabolic processes in the human body. This is clearly demonstrated in patients with thyroid hormone disorders. Hyperthyroidism leads to high circulating serum thyroid hormone levels. Patients complain of palpitations, excessive sweating, weight loss and can display swelling of thyroid gland, known as goiter. In contrast, decreased serum thyroid hormone levels due to hypothyroidism can result in weight gain, depression, atherosclerosis and hypertension. Even subtle changes in serum thyroid parameters in patients with subclinical thyroid disease can have important consequences on thyroid hormone related end-points, such as atherosclerosis, heart rate, depression and osteoporosis. Therefore, it is likely that small variations in genes involved in thyroid hormone metabolism that result in altered thyroid hormone bioactivity can also have effects on clinical end-points. This thesis focuses on the effect of thyroid hormone pathway genes on serum thyroid hormone levels and clinical endpoints using a candidate gene approach. In addition, associations between serum thyroid parameters and clinical endpoints, such as osteoporosis and hypertension are studied

Influence of enzalutamide on cabazitaxel pharmacokinetics: A Drug–Drug interaction study in metastatic castration-resistant prostate cancer (mCRPC) patients

Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug–drug interaction needs to be investigated. Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added. Results: A potential clinically relevant 22% (95% CI, 9%–34%; P ¼ 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0–24h of cabazitaxel was 181 ngh/mL (95% CI, 150–219 ngh/mL) in cycle 3 and 234 ngh/mL (95% CI, 209–261 ngh/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising. Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug–drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure

Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters

Thyroid hormone is a pleiotropic hormone with widespread biological actions. For instance, adequate levels of thyroid hormone are critical for the development of different tissues such as the central nervous system, but are also essential for the regulation of metabolic processes throughout life. The biological activity of thyroid hormone depends not only on serum thyroid hormone levels, but is also regulated at the tissue level by the expression and activity of deiodinases, which activate thyroid hormone or mediate its degradation. In addition, thyroid hormone transporters are necessary for the uptake of thyroid hormone into target tissues. With the discovery of monocarboxylate transporter 8 (MCT8) as a specific thyroid hormone transporter and the finding that mutations in this transporter lead to a syndrome of severe psychomotor retardation and elevated serum 3,3′,5-tri-iodothyronine levels known as the Allan-Herndon-Dudley syndrome, the interest in this area of research has greatly increased. In this review, we will focus on the molecular aspects of thyroid hormone transporters, including MCT8, MCT10, organic anion transporting polypeptides, and the effects of genetic variation in these transporters

High free thyroxine levels are associated with QTc prolongation in males

The literature on the effect of excess thyroid hormone on ventricular repolarization is controversial. To study whether free thyroxine (T4) and TSH are associated with QTc prolongation we conducted population-based cohort study. This study was conducted as part of the Rotterdam Study and included 365 men and 574 women aged 55 years and older with an electrocardiogram, who were randomly sampled for the assessment of thyroid status (free T4/TSH) at baseline, after exclusion of participants with hypothyroidism, use of antithyroid drugs, thyroid hormones or digoxin, left ventricular hypertrophy, and left and right bundle branch block. Endpoints were the length of the QTc interval and risk of borderline QTc prolongation. The associations were examined by means of linear and logistic regression analysis, adjusted for age and gender, diabetes mellitus, myocardial infarction, hypertension, and heart failure. Overall, there was