Prediction of liver volume – a population‐based approach to meta‐analysis of paediatric,adult and geriatric populations – an update

Liver volume is a critical scaling factor for predicting drug clearance in physiologically based pharmacokinetic modelling and for both donor/recipient graft size estimation in liver transplantation. The accurate and precise estimation of liver volume is therefore essential. The objective here was to extend an existing meta‐analysis using a non‐linear mixed effects modelling approach for the estimation of liver volume to other race groups and paediatric and geriatric populations. Interrogation of the PubMed® database was undertaken using a text string query to ensure as objective a retrieval of liver volume data for the modelling exercise as possible. Missing body size parameters were estimated using simulations from the Simcyp Simulator V13R1 for an age and ethnically appropriate population. Non‐linear mixed effect modelling was undertaken in Phoenix 1.3 (Certara) utilizing backward deletion and forward inclusion of covariates from fully parameterized models. Existing liver volume models based on body surface area (BSA) and body weight and height were implemented for comparison. The extension of a structural model using a BSA equation and incorporating the Japanese race and age as covariates and exponents on LV0 (θ _Baseline) and body surface area (θ _BSA), respectively, delivered a comparatively low objective function value. Bootstrapping of the original dataset revealed that the confidence intervals (2.5–97.5%) for the fitted (theta) parameter estimates were bounded by the bootstrapped estimates of the same. In conclusion, extension and re‐parameterization of the existing Johnson model adequately describes changes in liver volume using the body surface area in all investigated populations. Copyright © 2017 John Wiley & Sons, Ltd.     

An updated weight of evidence approach for deriving a health‐based guidance value for 4‐nonylphenol

4‐Nonylphenol (NP) is a persistent estrogen‐active compound. Human exposure to NP is primarily through water and food. Although risk assessments of NP have been conducted by the European Union and a few other countries, only the Danish Veterinary and Food Administration, in 2000, proposed a tolerable daily intake of 0.005 mg kg^?1 body weight (bw) day^?1. New data have been accumulated since then, prompting an update on the risk assessment of NP. A weight of evidence approach is recommended for use in scientific assessments by several agencies, e.g., European Food Safety Authority, etc. Based on the results of a weight of evidence approach, two methods were used to derive the health‐based guidance value (HBGV) for NP in this study, namely a no observed adverse effects level/lowest observable adverse effect level method, and a benchmark dose method. Considering the considerable uncertainty of benchmark dose model fitting of the available data, a tolerable daily intake value of 0.025 mg kg^?1 bw day^?1 was derived as a provisional HBGV for NP based on the lowest observable adverse effect level value of 15 mg kg^?1 bw day^?1 of the renal toxicity in rats, together with the uncertainty factor of 600. However, the HBGV of NP still needs further investigation.     

[18F]6‐fluoro‐3,4‐dihydroxy‐ l‐phenylalanine – recent modern syntheses for an elusive radiotracer

[¹⁸F]6‐fluoro‐3,4‐dihydroxy‐ l ‐phenylalanine ([¹⁸F]F‐DOPA) has been known to be a useful radiotracer for over 30 years. Its widespread clinical use has been hampered by the lack of a robust, high yielding synthesis. This review summarises new developments in radiochemistry that are providing solutions to long standing problems involved in the synthesis of this important but elusive radiotracer. Considerable advances in nucleophilic synthesis have been achieved by optimising multistep strategies and using both hypervalent iodine chemistry and transition metal‐mediated fluorinations allowing for the production of high specific activity [¹⁸F]F‐DOPA.     

Synthesis of a [14C]‐steroid intermediate: an application of a nonstabilized Horner–Wadsworth–Emmons olefination approach

Radiolabeled steroid derivative 1 was successfully prepared using a Horner–Wadsworth–Emmons approach: a [¹⁴C]‐label was efficiently incorporated into the C‐18 position of the molecule. Previously published procedures employing other olefination methods are either not applicable due to unavailability of [¹⁴C]‐precursors or suffer from poor reactivity.     

A new approach for 11C–C bond formation: Synthesis of 17α‐(3′‐[11C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol

A new approach for ¹¹C–C bond formation via a Sonogashira‐like cross‐coupling reaction of terminal alkynes with [¹¹C]methyl iodide was exemplified by the synthesis of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol. The LC‐purified title compound was obtained in decay‐corrected radiochemical yields of 27–47% (n=8) based on [¹¹C]methyl iodide within 21–27 min after EOB. In a typical synthesis starting from 9.6 GBq [¹¹C]methyl iodide, 1.87 GBq of 17α‐(3′‐[¹¹C]prop‐1‐yn‐1‐yl)‐3‐methoxy‐3,17β‐estradiol was synthesized in radiochemical purity >99%. The specific radioactivity ranged between 10 and 19 GBq/µmol, and the labeling position was verified by ¹³C‐NMR analysis of the corresponding ¹³C‐labeled compound. Copyright © 2003 John Wiley & Sons, Ltd.