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Dive into the research topics where Kati-Sisko Vellonen is active.

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Featured researches published by Kati-Sisko Vellonen.


European Journal of Pharmaceutical Sciences | 2003

Paracellular and passive transcellular permeability in immortalized human corneal epithelial cell culture model.

Elisa Toropainen; Veli-Pekka Ranta; Kati-Sisko Vellonen; Joni J. Palmgrén; Anu Talvitie; Mirka Laavola; Pekka Suhonen; Kaisa Mari Hämäläinen; Seppo Auriola; Arto Urtti

A cell culture model of human corneal epithelium (HCE-model) was recently introduced [Invest. Ophthalmol. Vis. Sci. 42 (2001) 2942] as a tool for ocular drug permeation studies. In this study, passive permeability and esterase activity of the HCE-model were characterised. Immortalised human corneal epithelial cells were grown on collagen coated filters under air-lift. The sensitivity of transcellular permeability to lipophilicity was tested in studies using nine beta-blockers. The size selectivity of the paracellular route was investigated using 16 polyethylene glycol oligomers (PEG). An effusion-like approach was used to estimate porosity and pore sizes of the paracellular space in HCE membrane. Permeability and degradation of fluorescein diacetate to fluorescein in HCE-cells was used to probe the esterase activity of the HCE-model. Drug concentrations were analyzed using HPLC (beta-blockers), LC-MS (PEGs), and fluorometry (fluorescein). Permeabilities were compared to those in the excised rabbit cornea. Penetration of beta-blockers increased with lipophilicity according to a sigmoidal relationship. This was almost similar to the profile in excised cornea. No apical to basolateral directionality was seen in the permeation of beta-blockers. Paracellular permeability of the HCE-model was generally slightly higher than that of the excised rabbit cornea. The HCE-model has larger paracellular pores, but lower pore density than the excised cornea, but the overall paracellular space was fairly similar in both models. The HCE-model shows significant esterase activity (i.e. fluorescein diacetate was converted to free fluorescein). These data on permeability of 27 compounds demonstrate that the barrier of the HCE-model closely resembles that of the excised rabbit cornea. Therefore, the HCE-model is a promising alternative corneal substitute for ocular drug delivery studies.


Pharmaceutical Research | 2009

Efflux Protein Expression in Human Retinal Pigment Epithelium Cell Lines

Eliisa Mannermaa; Kati-Sisko Vellonen; Tuomas Ryhänen; Katriina Kokkonen; Veli-Pekka Ranta; Kai Kaarniranta; Arto Urtti

PurposeThe objective of this study was to characterize efflux proteins (P-glycoprotein (P-gp), multidrug resistance proteins (MRP1–6) and breast cancer resistance protein (BCRP)) of retinal pigment epithelium (RPE) cell lines.MethodsExpression of efflux proteins in two secondary (ARPE-19, D407) and two primary (HRPEpiC and bovine) RPE cell lines was measured by quantitative RT-PCR and western blotting. Furthermore, activity of MRP1 and MRP5 of ARPE-19 cell line was assessed with calcein-AM and carboxydichlorofluorescein (CDCF) probes.ResultsSimilar efflux protein profile was shared between ARPE-19 and primary RPE cells, whereas D407 cell line was notably different. D407 cells expressed MRP2 and BCRP, which were absent in other cell lines and furthermore higher MRP3 transcript expression was found. MRP1, MRP4 and MRP5 were identified from all human RPE cell lines and MRP6 was not expressed in any cell lines. The pattern of efflux protein expression did not change when ARPE-19 cells were differentiated on filters. The calcein-AM and CDCF efflux tests provided evidence supporting MRP1 and MRP5 activity in ARPE-19 cells.ConclusionsMRP1, MRP4 and MRP5 are the main efflux transporters in RPE cell lines. There are differences in efflux protein expression between RPE cell lines.


Journal of Pharmaceutical Sciences | 2010

Effluxing ABC transporters in human corneal epithelium

Kati-Sisko Vellonen; Eliisa Mannermaa; Helen Turner; Marika Häkli; J. Mario Wolosin; Timo Tervo; Paavo Honkakoski; Arto Urtti

ATP-binding cassette (ABC) transporters are able to efflux their substrate drugs from the cells. We compared expression of efflux proteins in normal human corneal epithelial tissue, primary human corneal epithelial cells (HCEpiC), and corneal epithelial cell culture model (HCE model) based on human immortal cell line. Expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1-6 (MRP1-6) and breast cancer resistance protein (BCRP) was studied using quantitative RT-PCR, Western blot, and immunohistochemistry. Only MRP1, MRP5, and BCRP were expressed in the freshly excised human corneal epithelial tissue. Expression of MRP1 and MRP5 was localized predominantly in the basal cells of the central cornea and limbus. Functional efflux activity was shown in the cell models, but they showed over-expression of most efflux transporters compared to that of normal corneal epithelium. In conclusion, MRP1, MRP5, and BCRP are expressed in the corneal epithelium, but MDR1, MRP2, MRP3, MRP4, and MRP6 are not significantly expressed. HCE cell model and commercially available primary cells deviate from this expression profile.


European Journal of Pharmaceutical Sciences | 2010

Filter-cultured ARPE-19 cells as outer blood-retinal barrier model

Eliisa Mannermaa; Mika Reinisalo; Veli-Pekka Ranta; Kati-Sisko Vellonen; Heidi Kokki; Anni Saarikko; Kai Kaarniranta; Arto Urtti

Retinal pigment epithelium (RPE) regulates drug transfer between posterior eye segment and blood circulation, but there is no established RPE cell model for drug delivery studies. We evaluated ARPE-19 filter culture model for this purpose. Passive permeability of 6-carboxyfluorescein, betaxolol and FITC-dextran (40kDa) and active transport of 6-carboxyfluorescein, sodium fluorescein, rhodamine 123, cyclosporine A and digoxin in ARPE-19 model were investigated and compared with isolated bovine RPE-choroid tissue. In addition, barrier properties, and mRNA expression of RPE-specific and melanogenesis-related genes (RPE65, VMD2, CRALBP, OTX-2, MITF-A, TRP-1, tyrosinase) were measured in various culture conditions. The filter grown ARPE-19 cell model showed reasonable barrier properties (TER close to 100Omegacm(2)), but its permeability was slightly higher than that of isolated bovine RPE/choroid specimens. In active transport studies the ARPE-19 model mimics qualitatively the permeability profile of bovine RPE-choroid, but ARPE-19 model underestimates the importance of active transport relative to passive diffusion. Long-term filter-cultured ARPE-19 cells expressed various RPE-specific and melanogenesis-related genes at higher levels than the ARPE-19 cells cultured short-term in flasks. ARPE-19 model can be used to study drug permeation processes in the RPE.


Pharmaceutical Research | 2003

Ocular pharmacokinetic modeling using corneal absorption and desorption rates from in vitro permeation experiments with cultured corneal epithelial cells.

Veli-Pekka Ranta; Mirka Laavola; Elisa Toropainen; Kati-Sisko Vellonen; Anu Talvitie; Arto Urtti

AbstractPurpose. To determine corneal absorption and desorption rate constants in a corneal epithelial cell culture model and to apply them to predict ocular pharmacokinetics after topical ocular drug application. Method. In vitro permeation experiments were performed with a mixture of six β-blockers using an immortalized human corneal epithelial cell culture model. Disappearance of the compounds from the apical donor solution and their appearance in the basolateral receiver solution were determined and used to calculate the corneal absorption and desorption rate constants. An ocular pharmacokinetic simulation model was constructed for timolol with the Stella® program using the absorption and desorption rate constants and previously published in vivo pharmacokinetic parameters. Results. The corneal absorption rates of β-blockers increased significantly with the lipophilicity of the compounds. The pharmacokinetic simulation model gave a realistic mean residence time for timolol in the cornea (57 min) and the aqueous humor (90 min). The simulated timolol concentration in the aqueous humor was about 1.8 times higher than the previously published experimental values. Conclusions. The simulation model gave a reasonable estimate of the aqueous humor concentration profile of timolol. This was the first attempt to combine cell culture methods and pharmacokinetic modeling for prediction of ocular pharmacokinetics. The wider applicability of this approach remains to be seen.


European Journal of Pharmaceutics and Biopharmaceutics | 2015

Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development

Eva M. del Amo; Kati-Sisko Vellonen; Heidi Kidron; Arto Urtti

The aims of this research were to (1) create a curated universal database of intravitreal volumes of distribution (Vss, ivt) and clearances (CL ivt) of small molecular weight compounds and macromolecules and (2) to develop quantitative structure property relationship (QSPR) and pharmacokinetic models for the estimation of vitreal drug concentrations based on the compound structure. Vss, ivt and CL ivt values were determined from the available literature on intravitreal drug administration using compartmental models and curve fitting. A simple QSPR model for CL ivt of small molecular weight compounds was obtained with two descriptors: Log D7.4 and hydrogen bond donor capacity. The model predicted the internal and external test sets reliably with a mean fold error of 1.50 and 1.33, respectively (Q(2)Y=0.62). For 80% of the compounds the Vss, ivt was 1.18-2.28 ml; too narrow range for QSPR model building. Integration of the estimated Vss, ivt and predicted CL ivt parameters into pharmacokinetic simulation models allows prediction of vitreous drug concentrations after intravitreal administration. The present work presents for the first time a database of CL ivt and Vss, ivt values and the dependence of the CL ivt values on the molecular structure. The study provides also useful in silico tools to investigate a priori the intravitreal pharmacokinetic profiles for intravitreally injected candidate compounds and drug delivery systems.


Pharmaceutical Research | 2014

Challenges of using in vitro data for modeling P-glycoprotein efflux in the blood-brain barrier.

Noora Sjöstedt; Hanna Kortejärvi; Heidi Kidron; Kati-Sisko Vellonen; Arto Urtti; Marjo Yliperttula

The efficacy of central nervous system (CNS) drugs may be limited by their poor ability to cross the blood-brain barrier (BBB). Transporters, such as p-glycoprotein, may affect the distribution of many drugs into the CNS in conjunction with the restricted paracellular pathway of the BBB. It is therefore important to gain information on unbound drug concentrations in the brain in drug development to ensure sufficient drug exposure from plasma at the target site in the CNS. In vitro methods are routinely used in drug development to study passive permeability and p-glycoprotein efflux of new drugs. This review discusses the challenges in the use of in vitro data as input parameters in physiologically based pharmacokinetic (PBPK) models of CNS drug disposition of p-glycoprotein substrates. Experience with quinidine demonstrates the variability in in vitro parameters of passive permeability and active p-glycoprotein efflux. Further work is needed to generate parameter values that are independent of the model and assay. This is a prerequisite for reliable predictions of drug concentrations in the brain in vivo.


European Journal of Pharmaceutical Sciences | 2010

Monocarboxylate transport in human corneal epithelium and cell lines

Kati-Sisko Vellonen; Marika Häkli; Natalya Merezhinskaya; Timo Tervo; Paavo Honkakoski; Arto Urtti

Monocarboxylate transporters (MCTs) are transmembrane proteins capable of transferring lactate and other endogenous and exogenous monocarboxylates across the cell membrane. The aim of the present study was to assess the expression and transporter role of human MCT1, MCT3 and MCT4 in the corneal epithelium, corneal epithelial cell lines (primary HCEpiC and immortalized HCE cells) and isolated rabbit corneas. MCT1 and MCT4 were expressed in the human corneal epithelium and the cell lines at mRNA and protein levels. Cellular uptake studies showed saturable and pH-dependent l-lactic acid transport, which was inhibited by various monocarboxylates like diclofenac and flurbiprofen. The permeability of benzoic acid across the rabbit cornea was higher in absorptive direction and this directionality was diminished in the presence of monocarboxylate drug valproic acid. Monocarboxylate transport was functional in the human corneal epithelial cells and rabbit cornea and it may play a role in the ocular drug absorption.


Pharmaceutical Research | 2010

Prediction of the Corneal Permeability of Drug-Like Compounds

Heidi Kidron; Kati-Sisko Vellonen; Eva M. del Amo; Anita Tissari; Arto Urtti

ABSTRACTPurposeTo develop a computational model for optimisation of low corneal permeability, which is a key feature in ocular drug development.MethodsWe have used multivariate analysis to build corneal permeability models based on a structurally diverse set of 58 drug-like compounds.ResultsAccording to the models, the most important parameters for permeability are logD at physiologically relevant pH and the number of hydrogen bonds that can be formed. Combining these descriptors resulted in models with Q2 and R2 values ranging from 0.77 to 0.79. The predictive capability of the models was verified by estimating the corneal permeability of an external data set of 11 compounds and by using predicted permeability values to calculate the aqueous humour concentrations in the steady-state of seven compounds. The predicted values correlated well with experimental values.ConclusionThe developed models are useful in early drug development to predict the corneal permeability and steady-state drug concentration in aqueous humor without experimental data.


Journal of Controlled Release | 2014

A critical assessment of in vitro tissue models for ADME and drug delivery.

Kati-Sisko Vellonen; Melina Malinen; Eliisa Mannermaa; Astrid Subrizi; Elisa Toropainen; Yan-Ru Lou; Heidi Kidron; Marjo Yliperttula; Arto Urtti

Cultured cells are widely used in the evaluation of new drugs and drug delivery systems. Cells can be grown at different levels of complexity ranging from simple reductionist models to complex organotypic models. The models are based on primary, secondary or stem cell derived cell cultures. Generation of tissue mimics with cultured cells is a difficult task, because the tissues have well-defined morphology, complex protein expression patterns and multiple inter-linked functions. Development of organotypic cell culture models requires proper biomaterial matrix and cell culture protocols that are able to guide the cells to the correct phenotype. This review illustrates the critical features of the cell culture models and, then, selected models are discussed in more detail (epidermal, corneal epithelial, retinal pigment epithelium, and hepatocyte models). The cell models are critically evaluated paying attention to the level of characterization and reliability of in vivo translation. Properties of the cell models must be characterized in detail using multiple biological assays and broad sets of model drugs. Robust in vivo predictions can be achieved with well-characterized cell models that are used in combination with computational methods that will bridge the gap between in vitro cell experiments and physiological situation in vivo in the body.

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Arto Urtti

University of Eastern Finland

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Eva M. del Amo

University of Eastern Finland

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Eliisa Mannermaa

University of Eastern Finland

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Veli-Pekka Ranta

University of Eastern Finland

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Elisa Toropainen

University of Eastern Finland

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Marika Ruponen

University of Eastern Finland

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Paavo Honkakoski

University of Eastern Finland

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Helen Turner

Columbia University Medical Center

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J. Mario Wolosin

Icahn School of Medicine at Mount Sinai

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