Communications Biophysics

Contains reports on five research projects.National Science Foundation (Grant G-16526)National Institutes of Health (Grant MH-04737-02

A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions

All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies

The association of neighbourhood and individual social capital with consistent self-rated health: a longitudinal study in Brazilian pregnant and postpartum women.

BACKGROUND: Social conditions, social relationships and neighbourhood environment, the components of social capital, are important determinants of health. The objective of this study was to investigate the association of neighbourhood and individual social capital with consistent self-rated health in women between the first trimester of pregnancy and six months postpartum. METHODS: A multilevel cohort study in 34 neighbourhoods was performed on 685 Brazilian women recruited at antenatal units in two cities in the State of Rio de Janeiro, Brazil. Self-rated health (SRH) was assessed in the 1st trimester of pregnancy (baseline) and six months after childbirth (follow-up). The participants were divided into two groups: 1. Good SRH--good SRH at baseline and follow-up, and, 2. Poor SRH--poor SRH at baseline and follow-up. Exploratory variables collected at baseline included neighbourhood social capital (neighbourhood-level variable), individual social capital (social support and social networks), demographic and socioeconomic characteristics, health-related behaviours and self-reported diseases. A hierarchical binomial multilevel analysis was performed to test the association between neighbourhood and individual social capital and SRH, adjusted for covariates. RESULTS: The Good SRH group reported higher scores of social support and social networks than the Poor SRH group. Although low neighbourhood social capital was associated with poor SRH in crude analysis, the association was not significant when individual socio-demographic variables were included in the model. In the final model, women reporting poor SRH both at baseline and follow-up had lower levels of social support (positive social interaction) [OR 0.82 (95% CI: 0.73-0.90)] and a lower likelihood of friendship social networks [OR 0.61 (95% CI: 0.37-0.99)] than the Good SRH group. The characteristics that remained associated with poor SRH were low level of schooling, Black and Brown ethnicity, more children, urinary infection and water plumbing outside the house. CONCLUSIONS: Low individual social capital during pregnancy, considered here as social support and social network, was independently associated with poor SRH in women whereas neighbourhood social capital did not affect women's SRH during pregnancy and the months thereafter. From pregnancy and up to six months postpartum, the effect of individual social capital explained better the consistency of SRH over time than neighbourhood social capital

Adhesion of Pseudomonas fluorescens (ATCC 17552) to Nonpolarized and Polarized Thin Films of Gold

The adhesion of Pseudomonas fluorescens (ATCC 17552) to nonpolarized and negatively polarized thin films of gold was studied in situ by contrast microscopy using a thin-film electrochemical flow cell. The influence of the electrochemical potential was evaluated at two different ionic strengths (0.01 and 0.1 M NaCl; pH 7) under controlled flow. Adhesion to nonpolarized gold surfaces readily increased with the time of exposition at both ionic-strength values. At negative potentials (−0.2 and −0.5 V [Ag/AgCl-KCl saturated {sat.}]), on the other hand, bacterial adhesion was strongly inhibited. At 0.01 M NaCl, the inhibition was almost total at both negative potentials, whereas at 0.1 M NaCl the inhibition was proportional to the magnitude of the potential, being almost total at −0.5 V. The existence of reversible adhesion was investigated by carrying out experiments under stagnant conditions. Reversible adhesion was observed only at potential values very close to the potential of zero charge of the gold surface (0.0 V [Ag/AgCl-KCl sat.]) at a high ionic strength (0.1 M NaCl). Theoretical calculations of the Derjaguin-Landau-Verwey-Overbeek (DLVO) interaction energy for the bacteria-gold interaction were in good agreement with experimental results at low ionic strength (0.01 M). At high ionic strength (0.1 M), deviations from DLVO behavior related to the participation of specific interactions were observed, when surfaces were polarized to negative potentials

Identification of three novel ring expansion metabolites of KAE609 in rat, dog, and human, a new spiroindolone agent for the treatment of malaria

KAE609 is a potent, fast-acting, schizonticidal agent being developed for the treatment of malaria. Following oral dosing of KAE609 to rats and dogs, the major radioactive component in plasma was KAE609. An oxidative metabolite, M18, was the prominent metabolite in rat and dog plasma. KAE609 was well absorbed and extensively metabolized such that low levels of parent compound (≤ 11% of the dose) were detected in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways (≥ 93% of the dose) in the feces of rats and dogs. M37 and M23 were the major metabolites in rat and dog feces, respectively. Amongst the prominent metabolites of KAE609, the isobaric chemical species, M37, was observed, suggesting the involvement of an isomerization or rearrangement during biotransformation. Subsequent structural elucidation of M37 revealed that KAE609, a spiroindolone, undergoes an unusual C-C bond cleavage, followed by a 1, 2-acyl shift to form a ring expansion metabolite M37. The in vitro metabolism of KAE609 in hepatocytes was investigated to understand this novel biotransformation. The metabolism of KAE609 was qualitatively similar across the species studied, thus further investigation was conducted using human recombinant CYP enzymes. The ring expansion reaction was found to be primarily catalyzed by CYP3A4 yielding M37. M37 was then subsequently oxidized to M18 by CYP3A4, and hydroxylated to M23 primarily by CYP1A2. Interestingly, M37 was colorless while M18 and M23 showed orange yellow color. The source of the color of M18 and M23 was attributed to their extended conjugated system of double bonds in the structures