This review introduces two sets of research results, one regarding patients’ and consumers’ perceptions of the pharmacist profession and pharmacy function, and the other regarding factors that influence patients’ medication-taking behavior. First, as an example of what was examined from patients’ perspectives regarding the pharmacist profession and pharmacy function, an analysis of patient response data before the introduction of the family pharmacist/pharmacy system is presented. The results clarified that the quality of medication instruction influences patients’ evaluations of pharmacists and further affects their evaluation of pharmacies, and that the main factor influencing patients’ evaluation of pharmacies is their evaluation of the pharmacists. In particular, patients who continuously used the same pharmacist and the same pharmacy were highly statistically related, demonstrating the significance of recommending a family pharmacist/pharmacy. Next, regarding patients’ medication-taking behavior, an empirical study of Japanese patients regarding the two-dimensional influencing factors was conducted. These factors, which have been the focus of recent overseas studies, included intentional nonadherence, such as skipping a dose, and unintentional nonadherence, such as forgetting to take a dose. The main influences were found to be from unintentional nonadherence and intentional non-adherence, with excessive information seeking and motivation to acquire knowledge potentially exacerbating intentional nonadherence in particular, as well as differences across diseases. These findings may contribute to supporting medication adherence in patients. In collaboration with graduate and postgraduate research students, future studies will continue to examine patients’ and consumers’ perspectives on medication adherence.

Quantitative prediction of the potential for drug–drug interaction (DDI) is essential to guarantee the safety and efficacy of drugs. DDI screening, modeling, and prediction is standard practice in the pharmaceutical industry. This review describes our work on (1) the establishment of a standard framework for determining physiologically based pharmacokinetic (PBPK) model structures and parameters useful for quantitatively analyzing DDIs via hepatic organic anion transporting polypeptides (OATPs). By analyzing clinically observed DDIs involving several statins as substrates, and cyclosporin A and rifampicin as inhibitors, similar in vivo inhibition constants for OATPs by each inhibitor were obtained, regardless of the substrate. (2) We took a PBPK modeling-based approach to define rate-determining processes in hepatic elimination of several OATPs and CYP3A dual substrates using our clinical DDI data with specific inhibitors for OATPs and CYP3A. Essential in vivo parameters (the passive diffusion/active transport ratio in the uptake, and the fraction of intrinsic clearance in the total drug elimination from the hepatocytes) dominating the rate-determining process in hepatic elimination were estimated quantitatively. (3) Finally, using our clinical DDI data with rifampicin, we established a PBPK model for coproporphyrin I (CP-I), which is expected to act as an endogenous substrate (biomarker) supporting the prediction of DDI involving hepatic OATPs. Our PBPK modeling-based approach with several in vitro experiments using CP-I and OATP probe substrates (statins) demonstrated the usefulness of the translation of the effect of an OATP inhibitor on CP-I pharmacokinetics into that on OATP probe substrates in drug discovery and development.

Free radicals, such as hydroxyl radical, superoxide, and lipid-derived radical, have unpaired electrons, making them a highly reactive chemical species. They play important physiological roles, for example, in the removal of xenobiotic substances, such as bacteria and viruses, and in the production of chemical mediators, like prostaglandins and leukotrienes. However, excessive production of free radicals can cause structural defects in biomolecules like DNA and proteins, resulting in a loss of their normal functions. Hence, free radicals have been implicated in the onset and progression of various diseases such as cancer, atherosclerosis, and neurodegenerative diseases. However, there is very little clarity on the substantial amount, type, and location of free radicals in vivo, under pathological conditions. An investigation on the actual state of free radicals in vivo could lead to the diagnosis of pathological conditions and the elucidation of the mechanisms of their onset and progression; therefore, the development of in vivo radical detection methods is being widely pursued. Toward this end, nuclear medical imaging methods have recently attracted attention. In this study, we discuss the development of a nuclear medical imaging probe for the specific targeting of lipid radicals.

Retinoid-related orphan receptor alpha (RORα) participates in regulating several physiological processes, including metabolism and circadian rhythms. RORα is an important regulator of plasma cholesterol levels and is involved in lipid homeostasis. Its activation increases high-density lipoprotein (HDL) levels and metabolism of oxysterols. RORα-deficient mice develop atherosclerosis owing to decreased plasma HDL levels, increased expression of inflammatory cytokines, and ischemia/reperfusion-induced damage. The transcriptional activity of RORα is controlled by cholesterol and its derivatives, endogenous ligands that form transcription initiation complexes. Conversely, when intracellular cholesterol is reduced by lipid-lowering drugs such as statins, which inhibit cholesterol synthesis, the transcriptional activity of RORα is attenuated. Therefore, studies have focused on identifying target genes regulated by RORα involved in alleviating atherosclerosis to develop new therapies. Characterization of ligands, transcription-mediating factors, and transcription initiation complexes involved in the transcriptional regulation of RORα will facilitate the development of synthetic ligands and their potential applications in diseases such as atherosclerosis, dyslipidemia, and diabetes. In this review, we discuss the current literature on the structure and function of RORα, the target genes regulated by RORα, and the potential of RORα as a therapeutic target for atherosclerosis.

Microphysiological systems (MPSs) based on microfluidic devices are attracting attention as an alternative cell assay platform to animal experiments in drug discovery. When we use microfluidic devices for cell culture, it is possible to experiment with various culture conditions that are difficult with conventional cell culture methods, such as fabrication of microstructures for cell placement, temporal and spatial control of liquid factors and adhesive conditions, and physical stimulation by flow and expansion/contraction. MPSs, which use microfluidic technology to construct the structure and function of physiological biological tissues and organs, are being commercialized and put to practical use worldwide with the entry of venture companies and pharmaceutical companies. Although research on the practical application of MPS in Japan has lagged far behind the efforts of Western countries, the Japan Agency for Medical Research and Development (AMED) launched the MPS Development and Research Project in FY2017 and established a system for MPS commercialization through industry-government-academia collaboration. The project is characterized by the formation of a consortium involving many researchers not only from academia but also from manufacturing and pharmaceutical companies with the aim of commercializing MPS devices. By FY2021, the final year of this project, several MPSs were successfully positioned in various stages of commercialization. This paper introduces two MPSs that the author was involved in commercializing in collaboration with domestic companies within the project.

Blood brain barrier (BBB) is strong barrier specific to the brain vasculatures. BBB protects the brain from xenobiotics, while make it difficult to predict toxicokinetics/toxicodynamics, pharmacokinetics/pharmacodynamics, and efficiencies of new drugs in drug development. In this review, we will explain the physiological significance of BBB, the reason why the humanized BBB Micro Physiological System (MPS) is necessary, and the background technologies of BBB MPS. Because BBB MPS is the fusion of the engineering element technologies and the biological element technologies, we will explain the element technologies in both fields, respectively. We will also introduce the recent trends of BBB MPS to improve the human predictability: the shear stress in microfluidic models and the cellular architecture reproduction by three dimensional culture.

Microphysiological system (MPS) are “Cell/tissue culture systems that reproduce in vivo organ functions in vitro by placing organ compartments that mimic the physiological environment of various organs such as the liver, small intestine, and lungs in micro-spaces.” The MPS are attracting attention around the world as tools to improve human predictability in drug discovery research. In the U.S., in 2012, the NIH (National Institutes of Health) allocated a large budget to academia for research development of MPS. In Japan, the National Institute of Advanced Industrial Science and Technology and the NIHS (National Institute of Health Sciences) have been playing a central role in commercialization, performance evaluation, and standardization of MPS devices developed by academia for the liver, small intestine, kidney, and BBB as target organs/tissues in the AMED–MPS project that started in 2017. Pharmaceutical companies are beginning to utilize MPS in drug discovery research. However, MPS have only just been raised as a topic of discussion between regulatory authorities and pharmaceutical companies, and it will be necessary to overcome many barriers before data obtained by MPS can be included in drug approval documents and be widely accepted administratively. In this review, I would like to introduce cardiac safety evaluation as a concrete example to show what paths MPS should take to gain regulatory approval. In addition, I would like also to introduce human 3D heart tissue, which was developed in NIHS, as a cardiac MPS.

Sandhoff disease (SD) is a glycosphingolipid storage disease resulting from a genetic mutation in HEXB and associated deficiency in β-hexosaminidase activity. This defect causes abnormal accumulation of ganglioside GM2 and related glycolipids in lysosomes, resulting in progressive deterioration of the central nervous system. Hexb-knockout (Hexb^−/−) mice, an established animal model, show abnormalities similar to the severe phenotype seen in human infants. We used iPS cells derived from this mouse model (SD-iPSCs) to examine abnormal neuronal lineage differentiation and development in vitro during the asymptomatic phase of SD. Differentiation ability along the time axis appears to be altered in SD-iPSCs in which the differentiation ability of neural stem cells is promoted and differentiation into neurons is completed earlier, while the timing of differentiation into astrocytes is accelerated. This abnormal differentiation was suppressed by introducing the Hexb gene. These results indicate that the abnormal differentiation of SD-iPSCs into the nervous system reflects the pathogenesis of SD. Analysis using Hexb^−/− mice revealed that activated microglia causes astrogliosis at the early stage of development that can be ameliorated via immunosuppression. Furthermore, reactive astrocytes in the cortex of Hexb^−/− mice express adenosine A_2A receptors in the late inflammatory phase. Inhibition of this receptor resulted in a decrease in activated microglial cells and inflammatory cytokines/chemokines. These results suggest that the astrocyte A_2A receptor is important as a sensor that regulates microglial activation in the late inflammatory phase. Thus, our results provide new insights into the complex pathogenesis of SD.

It is crucial to evaluate the photostability of drugs. However, it requires a longer period of time to evaluate the photodegradation of compounds because extended light exposure to the compound is required to detect photodegradation products with the help of the commonly utilized technique of chromatography. Therefore, a simple and easy approach to estimate the photostability of the compound is required particularly for the initial screening of the drug candidates. It was reported in our previous manuscript that, focusing on ultraviolet–visible (UV/vis) spectrometry, the area under the spectrum curve in the ultraviolet-A (UVA) range (AUSC_UVA) are closely related to the photodegradation of indomethacin polymorphs. In this study, the solid-state UV/vis absorption spectra of compound A polymorphs, indomethacin complexes and some small molecule compounds were determined and analyzed to check the applicability of this method. AUSC_UVA are closely related to the photodegradation of compound A polymorphs as well as indomethacin. On the contrary, no close relation was observed between AUSC_UVA of indomethacin complexes and their photodegradation. Additionally, the result indicated that the differences in their solid-state UV/vis absorption spectra were observed between photosensitive and photostable compounds. Photosensitive compounds show absorption in UVA range, while photostable compounds exhibit less absorption. In conclusion, the solid-state UV/vis absorption spectra of small molecular compounds might provide the key information on the photosensitivity.

Simultaneous administration of enteral formula and phenytoin in the clinical setting is known to reduce the plasma concentration of phenytoin. In this study, we examined the binding of phenytoin with enteral formulas and its components by quantifying the free phenytoin concentration. Furthermore, we investigated the effect of enteral formulas on gastrointestinal absorption of phenytoin in rats. The free phenytoin rate was reduced in vitro when phenytoin and enteral formula or pectin, a dietary fiber in enteral formulas, were co-administered. In vivo, when phenytoin and the enteral formula Mei Balance R^® were co-administered, the time to maximum plasma concentration (T_max) after oral administration was significantly increased. Moreover, the area under the phenytoin concentration–time curve from time zero to 6 h (AUC_0–6 h) was significantly increased by co-administration of phenytoin with the enteral formula PG Soft EJ^®. These results showed the gastrointestinal absorption of phenytoin differs according to the type of enteral formula. In addition, we found the first time that plasma phenytoin levels increase when combined with enteral formula. Among the components of enteral formulas, in particular, milk protein delayed the absorption of phenytoin. Moreover, milk protein, casein and carrageenan tended to increase AUC_0–6 h. These results suggest the change in phenytoin concentration is due not only to the binding of enteral formula but also to the disintegration of components such as protein. Therefore, when co-administrated of phenytoin and enteral formula, phenytoin must be monitored frequently according to the enteral formula interaction.