Browsing by Subject "absorption"

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  • Tervahauta, Tuomas (Helsingfors universitet, 2015)
    Prodrugs are pharmacologically inactive molecules which undergo metabolic bioactivation in vivo to form pharmaceutically active agents. Prodrugs have been designed to improve so called drug-like properties of active parent compounds (APC) i.e. to increase solubility or absorption and to reduce first-pass metabolism etc. In this master's thesis the goal was to establish non-cell-based in vitro methods to study prodrug bioactivation. Four commercially available prodrugs (bambuterol, olmesartan medoxomil (OM), candesartan cilexetil (CC) and famciclovir) were used as test compounds. The prodrugs were incubated in liver and intestinal S9 fractions and blood plasma to study in vitro bioactivation of these prodrugs. Other metabolism of the prodrug and APC (nonproductive metabolism) was studied by comparing incubation with and without cofactors of metabolizing enzymes. Species differences was studied using human, rat and dog matrices. Prodrug concentrations were quantified from the incubation samples using liquid chromatography- tandem mass spectrometry (LC-MSMS) methods developed for this study. Additionally the effect of promoiety on passive permeability was studied with parallel artificial membrane permeability assay (PAMPA). All of the studied prodrugs produced at least low concentrations of APC in one or more incubations. Terbutaline (APC of bambuterol) formation was observed in human plasma and was concentration dependent which is consisted with the literature. Olmesartan and candesartan were formed in S9 fraction in high rate, but not in buffer: indicating enzyme mediated hydrolysis. However, based on literature CC hydrolysis was not expected to occur in intestinal S9 fractions. Penciclovir (APC of famciclovir) was formed only in presence of human or rat liver S9 fraction which was in line with the pre-existing literature. With the method used the nonproductive metabolism could not be estimated. In PAMPA bambuterol, famciclovir and OM had higher permeability than corresponding APCs whereas CC was only more permeable than candesartan in pH 7.4. The in vitro incubation used in this study can be used for screening prodrugs. However both low and high activation rates were observed thus the clinically relevant in vivo APC formation can be achieved with both high and low bioactivation in vitro. Studying the rate of prodrug formation alone estimations about clinically relevant bioactivation rates cannot be concluded. No clear signs of nonproductive could be seen with the prodrugs studied with current method. For the estimation of nonproductive metabolism, metabolite screening studies would need to be developed and conducted parallel to studies prescribed in this master's thesis.
  • Cao, Xiaowei; Lu, Peng; Leppäranta, Matti; Arvola, Lauri; Huotari, Jussi; Shi, Xiaohong; Li, Guoyu; Li, Zhijun (2021)
    Spectral albedo and light transmittance through snow, ice, and water were measured in Lake Wuliangsuhai (40 degrees 36 '-41 degrees 30 ' N, 108 degrees 43 '-108 degrees 70 ' E), Inner Mongolia, China, during winter 2016. Data on the weather, structure of lake ice, and geochemistry of water were also collected during the 60-day field program. The study lake is shallow (mean depth 1.0-1.5 m) with a large wetland area. Compared with polar lakes, solar elevation is higher, snow accumulation is much lower, and the ice has more sediment. The ice was all congelation ice with a mean thickness of 36.6 cm, corresponding to a mean air temperature of -9.6 degrees C. The mean daily broadband albedo and photosynthetically active radiation (PAR) band transmittance were 0.54 and 0.08 (bare ice), 0.74 and 0.04 (new snow), and 0.30 and 0.12 (melting period), respectively. The level of light allowed photosynthesis to occur to the bottom of the lake. The ice acted as a grey filter for the sunlight with a mean attenuation coefficient of 2.1 m(-1). These results expand our knowledge of the evolution of light transfer through ice and snow cover and its role in the ecology of lakes in temperate and arid areas.