Browsing by Subject "imeytyminen"

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  • Mannerström, Marika (University of Helsinki, 1994)
  • Saarela, Jouko (Finnish Environment Institute, 1997)
    Monographs of the Boreal Environment Research 3
  • Seuna, Pertti (Vesihallitus. National Board of Waters, 1983)
    Vesientutkimuslaitoksen julkaisuja 50, 29-40
    Infiltraatio ja sen riippuvuus eräistä aluetekijöistä
  • Koskenkorva, Tiina (Helsingfors universitet, 2012)
    Elucidation of transporter- and/or metabolic enzyme-mediated drug interactions is important part of early drug development. However the knowledge about clinical consequences of transporter-mediated drug-drug interactions is still limited and more investigation is needed to improve our understanding. MDR1 transporter, widely distributed on the pharmacokinetic barriers in the body (e.g. intestine) and has been shown no limit the bioavailability of drugs. Substrates of MDR1 are exposed to limited intestinal drug absorption and intestinal drug-drug interactions due to inhibition of the transporter. In predicting the clinical significance of an interaction, the principal obstacle has been the limited ability to appropriately scale the preclinical data into in vivo situation. In vitro-in vivo correlations on the extent of MDR1's influence on absorption and standardized predicting methods for drug-drug interactions using the inhibitory constants (IC50 and Ki) would greatly increase the value of in vitro studies. Current in vitro and in silico methods for prediction of the influence of MDR1 on intestinal absorption and related drug-drug interactions are discussed in the literature review. In addition, the latest regulatory draft guidances (FDA, EMA) are reviewed. Aliskiren has been shown to be a sensitive MDR1 substrate in vivo and high affinity substrate for the transporter in vitro. The objective of the experimental work was to study the MDR1-mediated transport of aliskiren and the related drug-drug interactions in vitro and in silico. Vesicular transport assay was used to obtain kinetic parameters for aliskiren (Km and Vmax) and inhibitor potencies (IC50) for ketoconazole, verapamil, itraconazole and its metabolite hydroxyitraconazole. Ki was further calculated for itraconazole and hydroxyitraconazole. Aliskiren showed high affinity to MDR1 transporter with a Km value 5 µM, consistent to what was reported previously in different assay systems. The interactions between aliskiren and the inhibitors in vitro correlated to the observed interactions in vivo in humans. In addition, hydroxyitraconazole was shown to be a potent inhibitor of MDR1-mediated transport of aliskiren in vitro. This suggests that hydroxyitraconazole may contribute to the pronounced interaction observed between aliskiren and itraconazole in a clinical interaction study. A compartmental absorption and transit (CAT) model with added enterocyte compartments and MDR1 efflux was used to describe the influence of MDR1 on intestinal absorption of aliskiren in humans. The integration of kinetic parameters (Km) from in vitro studies requires further optimization on how to describe the intracellular drug concentrations in the model. Aliskiren is however suitable MDR1 probe substrate to be used in in vitro and in vivo trials in humans and therefore gives a good basis for developing vitro-in vivo predictive models.
  • Nyrhilä, Alexandra (Helsingin yliopisto, 2021)
    Kipu vaikuttaa negatiivisesti eläimen hyvinvointiin, ja tuotantoeläinten kivunlievitys on tärkeää sekä eettisistä että taloudellisista syistä. Meloksikaami on tulehduskipulääke, jota käytetään Suomessa yleisesti vasikoilla esimerkiksi lievittämään kipua nupoutustoimenpiteen jälkeen ja vähentämään hengitystie- ja ripulioireita. Vaikka meloksikaamia käytetään paljon alle neljän viikon ikäisillä, ei-märehtivillä vasikoilla, on meloksikaamin farmakokinetiikasta hyvin vähän tutkimuksia tämän ikäisillä vasikoilla. Tutkielman kirjallisuuskatsausosiossa on perusteltu meloksikaamin käyttöä naudoilla ja vertailtu meloksikaamin farmakokinetiikkaa eri antoreiteillä ja eri ikäisillä vasikoilla aikaisemman tutkimustiedon perusteella. Tutkielman sisältämän alkuperäistutkimuksen tavoitteena oli selvittää, miten kerta-annos meloksikaamia käyttäytyy 7–14 vuorokauden ikäisillä vasikoilla suonensisäisen, nahanalaisen ja suun kautta annostellun lääkityksen jälkeen. Hypoteeseina oli, että meloksikaamin hyötyosuus on suuri ja eliminaatio hidasta, ja että maksimikonsentraatio plasmassa saavutetaan nopeammin nahanalaisella kuin peroraalisella antoreitillä. Tutkimukseen valittiin 30 tervettä Viikin tutkimustilalla syntynyttä lehmä- ja sonnivasikkaa, jotka olivat 5–16 vuorokauden ikäisiä. Vasikat satunnaistettiin kolmeen antoreittiryhmään: suonensisäinen (IV), nahanalainen (SC) ja suun kautta (PO). Meloksikaamia annettiin jokaisessa ryhmässä vasikan elopainon mukaan annoksella 0,5 mg/kg. Vasikoilta kerättiin verinäytteitä plasman meloksikaamipitoisuuden määrittämiseksi 5, 10, 15, 30, ja 45 minuutin sekä 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 ja 168 tunnin kuluttua meloksikaamin annostelusta. Näytteiden meloksikaamipitoisuudet tutkittiin nestekromatografian ja massaspektrometrian avulla. Farmakokineettisessä analyysissä käytettiin tilatonta mallia. Tutkimuksessa todettiin mm. seuraavat farmakokineettiset arvot: Cmax (SC 1,91 ± 0,27 μg/ml; PO 1,77 ± 0,16 μg/ml), tmax (SC 7,6 ± 2,8 h; PO 10 ± 5,7 h), AUC0-∞ (IV 237,4 ± 33,4 h × μg/ml; SC 230,7 ± 78,1 h × μg/ml; PO 230,5 ± 70,6 h × μg/ml) ja t1⁄2 (IV 79,2 ± 12,4 h; SC 84,6 ± 24,8 h; PO 84,8 ± 22,3 h). Biologiseksi hyötyosuudeksi F laskettiin SC-ryhmälle 0,972 ja PO-ryhmälle 0,971. Tutkimuksen farmakokineettisissä muuttujissa ei havaittu merkitseviä eroja eri antoreittien välillä (p < 0,05). Tutkimuksen perusteella 7–14 vuorokauden ikäisillä vasikoilla meloksikaamin eliminaatio on hitaampaa kuin vanhemmilla vasikoilla, minkä takia yksi 0,5 mg/kg annos voi lievittää vasikan kipua usean vuorokauden ajan. Eri antoreittien välillä ei ole merkitsevää eroa meloksikaamin vaikutusajan tai terapeuttisen plasmapitoisuuden kannalta 7–14 vuorokauden ikäisillä vasikoilla, ja meloksikaamin hyötyosuus on tämän ikäisillä vasikoilla hyvä sekä nahanalaisella että peroraalisella antoreitillä.
  • 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.
  • Harju, Päivi (University of Helsinki, 1999)