Prediction of Tissue-Plasma Partition Coefficients Using Microsomal Partitioning: Incorporation into Physiologically based Pharmacokinetic Models and Steady-State Volume of Distribution Predictions.

Drug distribution is a necessary component of models to predict human pharmacokinetics. A new membrane-based tissue-plasma partition coefficient (K p) method (K p,mem) to predict unbound tissue to plasma partition coefficients (K pu) was developed using in vitro membrane partitioning [fraction unbound in microsomes (f um)], plasma protein binding, and log P The resulting K p values were used in a physiologically based pharmacokinetic (PBPK) model to predict the steady-state volume of distribution (V ss) and concentration-time (C-t) profiles for 19 drugs. These results were compared with K p predictions using a standard method [the differential phospholipid K p prediction method (K p,dPL)], which differentiates between acidic and neutral phospholipids. The K p,mem method was parameterized using published rat K pu data and tissue lipid composition. The K pu values were well predicted with R 2 = 0.8. When used in a PBPK model, the V ss predictions were within 2-fold error for 12 of 19 drugs for K p,mem versus 11 of 19 for Kp,dPL With one outlier removed for K p,mem and two for K p,dPL, the V ss predictions for R 2 were 0.80 and 0.79 for the K p,mem and K p,dPL methods, respectively. The C-t profiles were also predicted and compared. Overall, the K p,mem method predicted the V ss and C-t profiles equally or better than the K p,dPL method. An advantage of using f um to parameterize membrane partitioning is that f um data are used for clearance prediction and are, therefore, generated early in the discovery/development process. Also, the method provides a mechanistically sound basis for membrane partitioning and permeability for further improving PBPK models. SIGNIFICANCE STATEMENT: A new method to predict tissue-plasma partition coefficients was developed. The method provides a more mechanistic basis to model membrane partitioning.

Development and validation of a novel questionnaire to describe and assess sensations and triggers associated with refractory and unexplained chronic cough.

INTRODUCTION: Refractory or unexplained chronic cough (RUCC) is a common clinical problem with no effective diagnostic tools. The Sensations and Triggers Provoking Cough questionnaire (TOPIC) was developed to characterise cough in RUCC versus cough in other conditions. METHODS: Content analysis of participant interviews discussing the sensations and triggers of chronic cough informed TOPIC development. Participants with chronic cough completed the draft-TOPIC (a subset repeating 5-7 days later), St George's Respiratory Questionnaire (SGRQ), Cough Severity Diary (CSD) and Global Rating of Change Scale. The draft-TOPIC item list was reduced in hierarchical and Rasch analysis to refine the questionnaire to the TOPIC. RESULTS: 49 items describing the triggers and sensations of cough were generated from participant interviews (RUCC n=14, chronic obstructive pulmonary disease (COPD) n=11, interstitial lung disease (ILD) n=10, asthma n=11, bronchiectasis n=3, cystic fibrosis n=7). 140 participants (median age 60.0 (19.0-88.0), female 56.4%; RUCC n=39, ILD n=38, asthma n=45, COPD n=6, bronchiectasis n=12) completed draft-TOPIC, where items with poor 'fit' for RUCC were removed to create TOPIC (8 trigger items, 7 sensation items). Median TOPIC score was significantly higher in RUCC (37.0) vs ILD (24.5, p=0.009) and asthma (7.0, p<0.001), but not bronchiectasis (20.0, p=0.318) or COPD (18.5, p=0.238), likely due to small sample sizes. The Rasch model demonstrated excellent fit in RUCC (χ2=22.04, p=0.85; PSI=0.88); as expected. When all participant groups were included, fit was no longer demonstrated (χ2=66.43, p=0.0001, PSI=0.89) due to the increased heterogeneity (CI=0.077). TOPIC correlated positively with SGRQ (r=0.47, p<0.001) and CSD (r=0.63, p<0.001). The test-retest reliability of TOPIC (intraclass correlation coefficient) was excellent (r=0.90, p<0.001). CONCLUSIONS: High TOPIC scores in the RUCC patients suggest their cough is characterised by specific sensations and triggers. Validation of TOPIC in cough clinics may demonstrate value as an aid to identify features of RUCC versus cough in other conditions.

Human NK cells proliferate and die in vivo more rapidly than T cells in healthy young and elderly adults.

NK cells are essential for health, yet little is known about human NK turnover in vivo. In both young and elderly women, all NK subsets proliferated and died more rapidly than T cells. CD56(bright) NK cells proliferated rapidly but died relatively slowly, suggesting that proliferating CD56(bright) cells differentiate into CD56(dim) NK cells in vivo. The relationship between CD56(dim) and CD56(bright) proliferating cells indicates that proliferating CD56(dim) cells both self-renew and are derived from proliferating CD56(bright) NK cells. Our data suggest that some dying CD56(dim) cells become CD16(+)CD56(-) NK cells and that CD16(-)CD56(low) NK cells respond rapidly to cellular and cytokine stimulation. We propose a model in which all NK cell subsets are in dynamic flux. About half of CD56(dim) NK cells expressed CD57, which was weakly associated with low proliferation. Surprisingly, CD57 expression was associated with higher proliferation rates in both CD8(+) and CD8(-) T cells. Therefore, CD57 is not a reliable marker of senescent, nonproliferative T cells in vivo. NKG2A expression declined with age on both NK cells and T cells. Killer cell Ig-like receptor expression increased with age on T cells but not on NK cells. Although the percentage of CD56(bright) NK cells declined with age and the percentage of CD56(dim) NK cells increased with age, there were no significant age-related proliferation or apoptosis differences for these two populations or for total NK cells. In vivo human NK cell turnover is rapid in both young and elderly adults.

ZnS nanocrystal cytotoxicity is influenced by capping agent chemical structure and duration of time in suspension.

As a result of their characteristic physical and optical properties, including their size, intense fluorescence, broad excitation, narrow emission and resistance to photobleaching, semiconductor nanocrystals are potentially useful for a variety of biological applications including molecular imaging, live-cell labeling, photodynamic therapy and targeted drug delivery. In this study, zinc sulfide (ZnS) semiconductor nanocrystals were synthesized in the 3 to 4 nm size range with selected capping agents intended to protect the nanocrystal core and increase its biological compatibility. We show that the biocompatibility of ZnS nanocrystals with primary murine splenocytes is influenced by the chemical structure of the outer capping agent on the nanocrystal. Additionally, the cytotoxicity of ZnS nanocrystals increases markedly as a function of time spent in suspension in phosphate-buffered saline (PBS). These data suggest that the potential therapeutic and/or biological use of ZnS nanocrystals is inherently dependent upon the proper choice of capping agent, as well as the conditions of nanocrystal preparation and storage.

Methods to Predict Volume of Distribution.

PURPOSE OF REVIEW: Prior to human studies, knowledge of drug disposition in the body is useful to inform decisions on drug safety and efficacy, first in human dosing, and dosing regimen design. It is therefore of interest to develop predictive models for primary pharmacokinetic parameters, clearance, and volume of distribution. The volume of distribution of a drug is determined by the physiological properties of the body and physiochemical properties of the drug, and is used to determine secondary parameters, including the half-life. The purpose of this review is to provide an overview of current methods for the prediction of volume of distribution of drugs, discuss a comparison between the methods, and identify deficiencies in current predictive methods for future improvement. RECENT FINDINGS: Several volumes of distribution prediction methods are discussed, including preclinical extrapolation, physiological methods, tissue composition-based models to predict tissue:plasma partition coefficients, and quantitative structure-activity relationships. Key factors that impact the prediction of volume of distribution, such as permeability, transport, and accuracy of experimental inputs, are discussed. A comparison of current methods indicates that in general, all methods predict drug volume of distribution with an absolute average fold error of 2-fold. Currently, the use of composition-based PBPK models is preferred to models requiring in vivo input. SUMMARY: Composition-based models perfusion-limited PBPK models are commonly used at present for prediction of tissue:plasma partition coefficients and volume of distribution, respectively. A better mechanistic understanding of important drug distribution processes will result in improvements in all modeling approaches.

A within-subject analysis of the effects of remote cueing on pelvic alignment in dancers.

Many professionals who treat and train dancers believe that good alignment at the pelvis can facilitate movement efficiency and reduce injury risk in a variety of dance genres. This study evaluated the effects of a remote cueing technique on pelvic alignment for dancers in a university-based professional training program. Two female dancers participated in 20-minute individualized observation and training sessions twice a week for eight weeks. Pelvic alignment improved to criterion levels for both dancers, suggesting that individualized approaches may have special utility in training dancers.