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Plasma protein binding is an important factor for the kinetics of drugs and how they act since it is the first step in drug distribution. Physiological changes in pregnancy, which include plasma composition, can affect drug binding and subsequent drug response. In the present study, we investigated the toxicokinetics (TK) and/or toxicodynamics (TD) of diclofenac and propranolol comparing pregnant Sparague-Dawley (SD) rats with non-pregnant SD rats in terms of protein binding and drug distribution. Diclofenac and propranolol are reported to bind to albumin and a1-acid glycoprotein (AGP), respectively. After a single administration of diclofenac, the area under plasma concentration-time curve (AUC) based on free diclofenac in pregnant rats was 3.9 times higher than that in non-pregnant rats. This difference is considered to be due to a lower concentration of serum albumin and a higher concentration of non-esterified fatty acid (NEFA) that inhibits drug binding to albumin, in pregnant rats. In histopathological examination, more severe gastrointestinal toxicity was observed in pregnant rats at 24 hr after dosing. This severe toxicity was likely to be correlated with the higher AUC. With respect to propranolol, the difference of the AUC based on free propranolol was not clear although the concentration of serum AGP was lower in pregnant rats. However, the binding analysis data suggested a difference of protein binding at a lower propranolol concentration range. Consequently, lowered serum proteins and increased NEFA in pregnant rats can lead to low protein binding, subsequent increase in free drug concentrations, and eventual increase in the TD of drugs. [ABSTRACT FROM AUTHOR]

The retina consists of several layers, and drugs can affect the retina and choroid separately. Therefore, investigating the target layers of toxicity can provide useful information pertaining to its modes of action. Herein, we compared gene expression profiles obtained via microarray analyses using samples of target layers collected via laser capture microdissection and samples of the whole globe of the eye of rats treated with N -methyl- N -nitrosourea. Pathway analyses suggested changes in the different pathways between the laser capture microdissection samples and the whole globe samples. Consistent with the histological distribution of glial cells, upregulation of several inflammation-related pathways was noted only in the whole globe samples. Individual gene expression analyses revealed several gene expression changes in the laser capture microdissection samples, such as caspase- and glycolysis-related gene expression changes, which is similar to previous reports regarding N -methyl- N -nitrosourea-treated animals; however, caspase- and glycolysis-related gene expressions did not change or changed unexpectedly in the whole globe samples. Analyses of the laser capture microdissection samples revealed new potential candidate genes involved in the modes of action of N -methyl- N -nitrosourea-induced retinal toxicity. Collectively, our results suggest that specific retinal layers, which may be targeted by specific toxins, are beneficial in identifying genes responsible for drug-induced ocular toxicity., (©2022 The Japanese Society of Toxicologic Pathology.)

The cyanobacterium semi-filamentous multicellular strain ABRG5-3 undergoes cell lysis as a unique feature that occurs due to growth condition changes from normal cultivation with shaking to static cultivation without shaking in liquid culture (Nishizawa et al., 2010). Microscopic observation and energy dispersive X-ray spectrometer (EDX) analysis have revealed that lysis is involved in the accumulation of polyphosphate compounds and the disintegration of thylakoid membranes in cells. Static cultivation, dark or red light exposure, and temperature (22 to 42 °C) conditions were found to be effective factors for the induction of lysis. Moreover, stress induced by salts, osmotic pressure with sucrose, and the depletion of nitrogen or phosphate in cultures also induced ABRG5-3 cell lysis. Based on these results, we discuss lysis and its utilization in the biotechnology industry.