Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

ABSTRACT Two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were compared in the rat to elucidate the actual differences between their pharmacokinetics and pharmacodynamics after single and repeated administration. Their inhibitory potencies were also compared in vitro. After intravenous administration (3 mg/kg), the elimination half-life (t 1/2␤ ) of entacapone (0.8 h) was clearly shorter than that of tolcapone (2.9 h). The striatum/serum ratio of tolcapone was 3-fold higher than that of entacapone. After a single oral dose (10 mg/kg), both entacapone and tolcapone produced an equal maximal degree of COMT inhibition in peripheral tissues, but tolcapone inhibited striatal COMT more effectively than did entacapone. After the 7-day treatment (10 mg/kg twice daily), COMT activity had recovered to a level of 67 to 101% of control within 8 h after the last dose of entacapone. In tolcapone-treated animals, there was still extensive COMT inhibition present in peripheral tissues, and the degree of inhibition was higher than that attained after a single dose. The pharmacokinetic-pharmacodynamic modeling revealed that a plateau of COMT inhibition near the maximal attainable inhibition was reached already by plasma concentrations below 2000 ng/ml, both with entacapone and tolcapone. Entacapone and tolcapone inhibited equally rat liver COMT in vitro with K i values of 10.7 and 10.0 nM, respectively. In conclusion, tolcapone has a longer duration of action and a better brain penetration than entacapone. The results also suggest that peripheral COMT is inhibited continuously when tolcapone is dosed at 12-h intervals, but this was not seen with entacapone. The second-generation catechol-O-methyltransferase (COMT, EC 2.1.1.6) inhibitors, entacapone and tolcapone, are indicated as adjuncts to standard levodopa-dopa decarboxylase inhibitor therapy in Parkinson's disease. They increase the bioavailability of levodopa by inhibiting its peripheral metabolism to an inactive metabolite, 3-O-methyldopa. COMT inhibitors improve the efficacy of the levodopa-dopa decarboxylase inhibitor therapy by prolonging the duration of action and the clinical benefit of levodopa Entacapone and tolcapone apparently behave differently both in experimental animals and humans. However, as a rule, entacapone and tolcapone have been studied only individually; their pharmacokinetics and pharmacodynamics have not been compared thoroughly after single and repeated dosing. Actually, very little is known about their pharmacodynamics in different tissues after repeated dosing. Furthermore, only the relationship between the plasma drug concentration and COMT activity in erythrocytes has been studied previously A few available studies on entacapone and tolcapone in rats suggest that entacapone is eliminated faster than tolcapone and its oral bioavailability is lower than that of tolcapone. After intravenous administration of 10 mg/kg tolcapone, the t 1/2 was 0.9 h and total clearance 470 ml ϫ h Ϫ1 ϫ kg Ϫ1 . The oral bioavailability was 48% for 20 mg/kg and 56% for 40 mg/kg The time course of COMT activity in different tissues has ABBREVIATIONS. COMT, catechol-O-methyltransferase; t 1/2␤ , elimination half-life (␤-phase); S-COMT; soluble catechol-O-methyltransferase; MB-COMT, membrane-bound catechol-O-methyltransferase; AUE, area under the effect-time curve; AUC, area under the plasma drug concentration-time curve; C 0 , initial plasma concentration; E 0 , baseline effect; E max , maximum attainable effect

Childhood socioeconomic status and lifetime health behaviors : The Young Finns Study

Background: Differences in health behaviors partly explain the socioeconomic gap in cardiovascular health. We prospectively examined the association between childhood socioeconomic status (SES) and lifestyle factors in adulthood, and the difference of lifestyle factors according to childhood SES in multiple time points from childhood to adulthood. Methods and results: The sample comprised 3453 participants aged 3-18 years at baseline (1980) from the longitudinal Young Finns Study. The participants were followed up for 31 years (N = 1675-1930). SES in childhood was characterized as reported annual family income and classified on an 8-point scale. Diet, smoking, alcohol intake and physical activity were used as adult and life course lifestyle factors. Higher childhood SES predicted a healthier diet in adulthood in terms of lower consumption of meat (beta +/- SE -3.6 +/- 0.99, p <0.001), higher consumption of fish (1.1 +/- 0.5, p = 0.04) and higher diet score (0.14 +/- 0.044, p = 0.01). Childhood SES was also directly associated with physical activity index (0.059 +/- 0.023, p = 0.009) and inversely with the risk of being a smoker (RR 0.90 95%CI 0.85-0.95, p <0.001) and the amount of pack years (-0.47 +/- 0.18, p = 0.01). Life course level of smoking was significantly higher and physical activity index lower among those below the median childhood SES when compared with those above the median SES. Conclusions: These results show that childhood SES associates with several lifestyle factors 31 years later in adulthood. Therefore, attention could be paid to lifestyle behaviors of children of low SES families to promote cardiovascular health. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Dietary Pattern Trajectories from Youth to Adulthood and Adult Risk of Impaired Fasting Glucose: A 31-year Cohort Study

ContextThe influence of dietary pattern trajectories from youth to adulthood on adult glucose metabolism is unknown.ObjectiveTo identify dietary pattern trajectories from youth to adulthood and examine their associations with adult impaired fasting glucose (IFG).MethodsThirty-one-year population-based cohort study among 1007 youths aged 3-18 years at baseline in Finland. Diet intake was assessed in 1980, 1986, 2001, 2007, and 2011. Group-based trajectory modelling was used to identify dietary pattern (identified by factor analysis) trajectories. Adult IFG was measured by the latest available data from 2001, 2007, and 2011.ResultsAmong 1007 participants, 202 (20.1%) developed IFG and 27 (2.7%) developed type 2 diabetes in adulthood (mean follow-up of 30.7 years; mean [SD] age 40.5 [5.0] years). Three dietary patterns were identified at baseline and were retained in 1986 and 2001: “Traditional Finnish,” “High carbohydrate,” and “Vegetables and dairy products.” Three different patterns were identified in 2007, which remained similar in 2011: “Traditional Finnish and high carbohydrate,” “Red meat,” and “Healthy.” Trajectories of increased or stably medium “red meat” pattern scores from youth to adulthood were detrimentally associated with IFG (relative risk 1.46, 95% CI 1.12-1.90 for Medium (M)-stable/M-large increase vs low-stable trajectory) after adjusting for confounders. This association was slightly reduced after further adjusting for long-term dietary fiber intake.ConclusionTrajectories of an increased or stably moderate adherence to a “red meat” dietary pattern from youth to adulthood are associated with higher risk of adult IFG. This association is partly explained by low dietary fiber intake.</p

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms