The
sensitivity to drugs and their disposition are changed depending on the
circadian time. Hence, choosing appropriate times of day to administer drugs enables
to enhance the therapeutic index of pharmacotherapy. On the other hand, various
disease conditions also exhibit circadian changes in symptom intensity. Several
therapeutic approaches are facilitated by the identification of chemical
compound targeted to key molecules that cause circadian exacerbation of disease
events. The author describes the current understanding of the role of the
circadian biological clock in regulating drug efficacy and
disease condition, and also presents ‘chrono-pharmaceutical’ strategy for treatment
of diseases and drug development.
Tyrosine kinase 2 (Tyk2)
is a member of the Janus family of protein tyrosine kinases (JAKs). Tyk2 associates
with interferon (IFN)-α,
IFN-β, interleukin (IL)-6, IL-10, IL-12, and IL-23 receptors and
mediates their downstream signaling pathways. The authors summarize that Tyk2
plays crucial roles in the differentiation, maintenance, and function of T
helper 1 (Th1) and Th17 cells and that its dysregulation in autoimmune and/or inflammatory
diseases using Tyk2-deficient mice and cells. The authors further describe that
Tyk2 inhibition has great potential for clinical application in the management
of a variety of immune-relating diseases.
This Current Topics includes 5 reviews, and the authors for individual reviews were invited to contribute papers updating/improving readers’ understanding of the nuclear receptors- and drug-metabolizing enzymes-mediated inter-individual differences. Nuclear receptors (e.g., ERα/β, PPARβ/δ, and RORα) are basically ligand-inducible and are known to be involved in the regulation of numerous physiological processes. At the post-transcriptional level, some microRNAs are involved in the regulation of CYP3A protein expression. In addition, at the post-translational levels, there are functional protein-protein interactions between different kinds of drug-metabolizing enzymes i.e., P450 and UGT, which results in modulation of the enzyme(s) activities.
Cilostazol is metabolized to two active metabolites in humans. This
study
investigated the influence of the plasma concentrations of cilostazol and the
metabolites on pulse rate in patients with cerebral infarction. Polymorphisms of metabolic enzymes significantly influenced plasma
disposition of OPC-13015, a metabolite by CYP3A4, and OPC-13213, another metabolite by CYP3A5 and CYP2C19. A
multiple regression model, consisting of factors of the plasma concentration of
OPC-13015, levels of blood urea nitrogen, and pulse rate at the start of cilostazol
therapy explained 55.5% of the interindividual variability of the changes in
pulse rate before and after the treatment.
Aniline and its dimethyl
derivatives reportedly become haematotoxic after metabolic N-hydroxylation
of their amino groups. The elimination rate of 3,5-dimethylaniline based on rat
plasma versus time curves was rapid compared with that of 2,6-dimethylaniline after
single oral doses of 25 mg/kg. The areas under the curve of unmetabolized
(remaining) dimethylaniline derivatives estimated using pharmacokinetic models
showed an apparently positive correlation with the reported lowest-observed-effect
levels for haematotoxicity of these chemicals. These results suggest that the
presence of a methyl group at the C2-positon may generally suppress
fast metabolic rates of dimethylaniline derivatives that promote metabolic
activation reactions at NH2 moieties.