This work examines the inter-relationship between the unbound drug fractions in blood and brain homogenate, passive membrane permeability, P-glycoprotein (Pgp) efflux ratio, and log octanol/water partition coefficients (cLogP) in determining the extent of central nervous system (CNS) penetration observed in vivo. The present results demonstrate that compounds often considered to be Pgp substrates in rodents (efflux ratio greater than 5 in multidrug resistant Madin-Darby canine kidney cells) with poor passive permeability may still exhibit reasonable CNS penetration in vivo; i.e., where the unbound fractions and nonspecific tissue binding act as a compensating force. In these instances, the efflux ratio and in vitro blood-brain partition ratio may be used to predict the in vivo blood-brain ratio. This relationship may be extended to account for the differences in CNS penetration observed in vivo between mdr1a/b wild type and knockout mice. In some instances, cross-species differences that might initially seem to be related to differing transporter expression can be rationalized from knowledge of unbound fractions alone. The results presented in this article suggest that the information exists to provide a coherent picture of the nature of CNS penetration in the drug discovery setting, allowing the focus to be shifted away from understanding CNS penetration toward the more important aspect of understanding CNS efficacy.Within the modern drug discovery paradigm, drug metabolism and pharmacokinetics (DMPK) play an integral role in the process of compound selection and progression. Much of the impact of DMPK has been caused by its transformation from a largely descriptive discipline to that of a predictive science, fuelled by advances in bioanalysis and in vitro techniques. Hence discovery DMPK provides a powerful means for assessing the risks of taking potential assets into development.Nevertheless, the development of molecules targeted at the central nervous system (CNS) remains a significant challenge caused by the increased regulation and protection afforded to the brain over other organs of the body. The major knowledge gaps are 1) understanding the physicochemical features that determine CNS penetration, 2) understanding the impact of the blood-brain barrier (BBB) on CNS uptake, and 3) providing a coherent measure of CNS penetration that can be related to drug efficacy. Regarding the latter point, although it is important to develop a link between the pharmacokinetics of a molecule and the biophase, arguably the critical issue is one of sufficient access of free drug to the requisite site of action.Numerous models and measures of CNS uptake are available to assist in the search for centrally active agents. In situ brain perfusion techniques have highlighted the good correlation between increasing lipophilicity and CNS permeability. Polar drugs that are subject to paracellular absorption such as atenolol (logD oct,7.4 Ϫ2.1; Artursson, 1990) and sumatriptan (logD oct,7.4 Ϫ1.5;Pascual and Munoz, 2005) show...

What are the novel findings of this work? Preterm delivery occurred in a higher proportion of women with SARS-CoV-2 infection in the PAN-COVID and AAP-SONPM registries compared to contemporaneous and historical national data from uninfected women in the UK and USA. The majority of preterm deliveries occurred between 32 + 0 and 36 + 6 weeks' gestation. SARS-CoV-2 infection in pregnancy did not appear to be associated with a clinically significant effect on fetal growth, adverse neonatal outcome or the rate of stillbirth. Although maternal death was uncommon, the rate was higher than expected based on UK and USA population data, which is likely explained by underascertainment of women affected by milder or asymptomatic infection in pregnancy in the PAN-COVID study, although not in the AAP-SONPM study. What are the clinical implications of this work? Pregnant women should be counseled that SARS-CoV-2 infection increases the risk of preterm delivery but not stillbirth, early neonatal death or a small baby. Healthcare providers should recommend SARS-CoV-2 vaccination in pregnant women and women planning pregnancy, alongside enhanced social distancing.

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