11 research outputs found
全身暴露およびインビトロ結合試験を基にした,ドパミンD2受容体拮抗薬およびヒスタミンH1受容体拮抗薬の中枢における受容体占有率予測
学位の種別: 論文博士審査委員会委員 : (主査)東京大学教授 楠原 洋之, 東京大学教授 富田 泰輔, 東京大学講師 前田 和哉, 東京大学講師 高田 龍平, 東京大学講師 山本 武人University of Tokyo(東京大学
Photoelectric Dye, NK-5962, as a Potential Drug for Preventing Retinal Neurons from Apoptosis: Pharmacokinetic Studies Based on Review of the Evidence
NK-5962 is a key component of photoelectric dye-based retinal prosthesis (OUReP). In testing the safety and efficacy, NK-5962 was safe in all tests for the biological evaluation of medical devices (ISO 10993) and effective in preventing retinal cells from death even under dark conditions. The long-term implantation of the photoelectric dye-coupled polyethylene film in the subretinal space of hereditary retinal dystrophic (RCS) rats prevented neurons from apoptosis in the adjacent retinal tissue. The intravitreous injection of NK-5962 in the eyes of RCS rats, indeed, reduced the number of apoptotic cells in the retinal outer nuclear layer irrespective of light or dark conditions. In this study, we reviewed the in vitro and in vivo evidence of neuroprotective effect of NK-5962 and designed pharmacokinetic experiments. The in vitro IC50 of 1.7 μM, based on the protective effect on retinal cells in culture, could explain the in vivo EC50 of 3 μM that is calculated from concentrations of intravitreous injection to prevent retinal neurons from apoptosis. Pharmacokinetics of NK-5962 showed that intravenous administration, but not oral administration, led to the effective concentration in the eye of rats. NK-5962 would be a candidate drug for delaying the deterioration of retinal dystrophy, such as retinitis pigmentosa
Prediction of CNS occupancy of dopamine D2 receptor based on systemic exposure and in vitro experiments
Prediction of CNS occupancy of dopamine D2 receptor based on systemic exposure and in vitro experiments
The effect of drugs in the central nervous system (CNS) is closely related to occupancy of their target receptor. In this study, we integrated plasma concentrations, in vitro/in vivo data for receptor or protein binding, and in silico data, using a physiologically based pharmacokinetic model, to examine the predictability of receptor occupancy in humans. The occupancy of the dopamine D2 receptor and the plasma concentrations of the antipsychotic drugs quetiapine and perospirone in humans were collected from the literature or produced experimentally. Association and dissociation rate constants and unbound fractions in the serum and brain were determined in vitro/in vivo using human D2 receptor-expressing membrane fractions, human serum and mouse brain. The permeability of drugs across the blood–brain barrier was estimated based on their physicochemical properties. The effect of a metabolite of perospirone, ID-15036, was also considered. The time profiles of D2 receptor occupancy following oral dose of quetiapine and perospirone predicted were similar to the observed values. This approach could assist in the design of clinical studies for drug development and the prediction of the impact of drug–drug interactions on CNS function in clinical settings
Corrigendum to “Quantitative prediction of histamine H1 receptor occupancy by the sedative and non-sedative antagonists in the human central nervous system based on systemic exposure and preclinical data” [Drug Metab Pharmacokinet 32 (2017) 135–144]
Photoelectric Dye, NK-5962, as a Potential Drug for Preventing Retinal Neurons from Apoptosis: Pharmacokinetic Studies Based on Review of the Evidence
Effect of Coadministration of Single and Multiple Doses of Rifampicin on the Pharmacokinetics of Fexofenadine Enantiomers in Healthy Subjects
Recommended from our members
Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides.
Naturally occurring peptides with high membrane permeability often have ester bonds on their backbones. However, the impact of amide-to-ester substitutions on the membrane permeability of peptides has not been directly evaluated. Here we report the effect of amide-to-ester substitutions on the membrane permeability and conformational ensemble of cyclic peptides related to membrane permeation. Amide-to-ester substitutions are shown to improve the membrane permeability of dipeptides and a model cyclic hexapeptide. NMR-based conformational analysis and enhanced sampling molecular dynamics simulations suggest that the conformational transition of the cyclic hexapeptide upon membrane permeation is differently influenced by an amide-to-ester substitution and an amide N-methylation. The effect of amide-to-ester substitution on membrane permeability of other cyclic hexapeptides, cyclic octapeptides, and a cyclic nonapeptide is also investigated to examine the scope of the substitution. Appropriate utilization of amide-to-ester substitution based on our results will facilitate the development of membrane-permeable peptides
Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis
Misfolding and aggregation of transthyretin
are implicated in the
fatal systemic disease known as transthyretin amyloidosis. Here, we
report the development of a naringenin derivative bearing two chlorine
atoms that will be efficacious for preventing aggregation of transthyretin
in the eye. The amyloid inhibitory activity of the naringenin derivative
was as strong as that of tafamidis, which is the first therapeutic
agent targeting transthyretin in the plasma. X-ray crystal structures
of the compounds in complex with transthyretin demonstrated that the
naringenin derivative with one chlorine bound to the thyroxine-binding
site of transthyretin in the forward mode and that the derivative
with two chlorines bound to it in the reverse mode. An ex vivo competitive
binding assay showed that naringenin derivatives exhibited more potent
binding than tafamidis in the plasma. Furthermore, an in vivo pharmacokinetic
study demonstrated that the dichlorinated derivative was significantly
delivered to the eye
Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis
Misfolding and aggregation of transthyretin
are implicated in the
fatal systemic disease known as transthyretin amyloidosis. Here, we
report the development of a naringenin derivative bearing two chlorine
atoms that will be efficacious for preventing aggregation of transthyretin
in the eye. The amyloid inhibitory activity of the naringenin derivative
was as strong as that of tafamidis, which is the first therapeutic
agent targeting transthyretin in the plasma. X-ray crystal structures
of the compounds in complex with transthyretin demonstrated that the
naringenin derivative with one chlorine bound to the thyroxine-binding
site of transthyretin in the forward mode and that the derivative
with two chlorines bound to it in the reverse mode. An ex vivo competitive
binding assay showed that naringenin derivatives exhibited more potent
binding than tafamidis in the plasma. Furthermore, an in vivo pharmacokinetic
study demonstrated that the dichlorinated derivative was significantly
delivered to the eye