<p>Drug-drug interactions (DDIs) occur when multiple drugs are used concurrently. Caused by one drug inhibiting or inducing the metabolism of a second drug, DDIs often alter plasma concentrations and could seriously impact efficacy and safety of co-administered medications. Cytochrome P450 (CYP), a superfamily of enzymes, plays an important role in metabolizing a majority of FDA approved drugs currently on the market. 70% of predicable DDIs are associated with CYP enzymes inhibition. In-silico methods are increasingly adopted as a cost-effective complement to guide and prioritize efforts in drug discovery. Recent emerging applications of artificial intelligence algorithms have demonstrated promising results capable of prioritizing the selection of large chemical libraries, thereby outlining the future of in-silico methods assisting in drug discovery. Nevertheless, current methods rely on molecular descriptors that almost exclusively focus on chemical properties and atomic structures that fail to capture critical conformation and biological interaction related properties. There is also a lack of trainable molecular descriptors with feature specificity that reflect detailed protein-ligand binding energy and enable biological activity prediction. The overall objective of this dissertation is to understand molecular biological binding activity through electronic structure-based local descriptors derived from quantum based conceptual density functional theory (CDFT). This method will be used to assess the correlation of intermolecular interaction energy with ligand-protein binding with 2D feature maps reduced from the 4D molecular surfaces of the binding site and ligand (3D molecular surface with 1D electronic property). Additionally, it will be used to explore the possibility of predicting CYP related DDIs using descriptors generated using first principles including protein-ligand binding with specificity and strength and deep learning algorithms. Using quantum chemistry to interpret topological molecular information residing on 3D molecular surface permits the extraction of interacting features directly from the ligand structure. To achieve that, a set of curatable data containing consistent measurements was accessed through publicly accessible libraries. A series of novel Manifold Embedding of Molecular Surface (MEMS) descriptors were generated containing local electronic properties residing on the 3D molecule structure surface of each ligand using manifold learning. Major information were captured featuring electronic characteristics on the molecular 3D surface. Shape context was employed to derive transnational invariance feature vectors from MEMS with high granularity, thus preserving molecular information with specificity. DeepSet was utilized to perform permutation equivariance model training and validation. Powerful model learning is observed with an F-measure for all targets above 75% with the highest of 87% from external testing. Despite their promising prediction performance, molecular conformation changes and analytical featurization methods need to be implemented to expand model applicability and improve model reliability.</p>

The aryl hydrocarbon receptor is a ligand-activated transcription factor that is involved in many important functions in the body. To study the role and function of AHR, an abundant amount of in vitro expressed and purified protein is needed. A baculovirus insect expression system is commonly employed to express AHR, however, there are several drawbacks with this method, such as mutation potential and high cost. A better in overexpression system is needed and we hypothesize that Pichia pastoris, a yeast expression system, could stably express AHR and ARNT (aryl hydrocarbon receptor nuclear translocator) in sufficient amount with reasonable cost. Codon optimized human AHR and ARNT genes were separately transformed into the Pichia pastoris genome and expressed. Co-immunoprecipitation, gel-shift assay and western analysis indicate Pichia pastoris was able to stably overexpress functional AHR and ARNT proteins in comparable yield and lower cost compared to baculovirus insect expression system and the expressed proteins were used to develop a new in vitro method to study AHR and ARNT binding. Pharmacokinetic studies were performed to investigate the role of AHR in rutacarpine-caffeine interactions. Oral RUT pretreatment was shown to reduce oral caffeine area under the curve (AUC) in rats, due to an increase in caffeine clearance (CL) and a decrease in oral bioavailability (F). RUT, an AHR ligand, increases caffeine CL by inducing Cyp1A2 enzyme, but the mechanism by which RUT reduces caffeine F is not understood. We hypothesize that it is also mediated via AHR pathway. To test the hypothesis, wild type (WT) and AHR knock out (KO) mice were administered caffeine IV and orally, with and without VEH or RUT pretreatment. As expected, PK data show higher caffeine CL and lower F values in WT, but similar CL and F values in AHR KO mice, upon RUT co-administration. Rats study, in which with pretreatment of vehicle, AHR ligands: RUT, beta-naphthoflavone or indole-3-carbinol before caffeine was dosed orally is consistent with mice study, that all three AHR agonists tested were able to reduce oral caffeine AUCs in rats. RUT reduces caffeine’s oral bioavailability is through AHR signaling pathway, however, However, the mechanism by which AHR mediates the reduced caffeine F is not known.

京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第24559号 / 薬科博第176号 / 新制||薬科||19(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 馬見塚 拓, 教授 山下 富義, 教授 金子 周司 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

This study set out to review and analyse aspects of antidepressant prescribing in children and adolescents in a section of the private health care sector of South Africa. The research was conducted in two phases, namely a literature review and an empirical investigation. The aim of the literature review was to provide background to the study by conceptualising antidepressants. The empirical review followed a retrospective, descriptive, observational design. The data employed in the study was obtained from the medicine claims database of a South African Pharmaceutical Benefit Management (PBM) company. The study population consisted of 3 611 children and adolescents receiving ≥1 antidepressants from 1 January 2010 to 31 December 2010. Basic descriptive statistics, such as frequency, prevalence, average, weighted average, standard deviation, weighted standard deviation, median, effect sizes, prescribed daily dosages and DU95% methodology were used to characterise the study sample, and were calculated using the Statistical Analysis System SAS® for Windows 9.3® program. The data were used to determine the prescribing patterns of antidepressants with regard to age, gender, geographic area, type of prescriber, the comparison of prescribed daily dosages vs. recommended daily dosages, and the prevalence of potential drug-drug interactions. Potential drug-drug interactions were identified and compiled by using various interaction compendia, whereas recommended daily dosages were identified by cross-referencing various dosage compendia. The study population consisted of 1 850 girls and 1 761 boys. The mean age of girls was 13.7 ± 3.9 years, vs. 12.3 ± 3.8 years for boys (d = 0.4). A total of 11 735 prescriptions containing 12 272 antidepressants were documented in 2010. Results of the study furthermore showed that the average number of prescriptions claimed per patient increased with age, from an average of 1.0 ± 0.28 among those up to the age of 2 years, to an average of 3.4 ± 3.21 among those 16 to 18 years of age. Prescribing with regard to age groups differed, rising gradually from birth and peaking at middle childhood for boys, whereas antidepressant use in girls increased from birth up to 6 years of age, reaching a plateau and increases again from age 13 and onward. Approximately 25% (n = 12 272) of antidepressants prescribed were either not indicated in children, or the dosages were deemed too high. More than 50% (n = 12 272) of antidepressants prescribed were in the Gauteng province. The SSRIs (selective serotonin re-uptake inhibitors) and the TCAs (tricyclic antidepressants) were the most prescribed antidepressants in both gender groups. The male-to-female ratio for the selective serotonin re-uptake inhibitors was 0.9, compared to 1.2 for the tricyclic antidepressants. The top three antidepressants prescribed were imipramine (21.8%), citalopram (15.3%) and escitalopram (14.7%, n = 12 272). Potential DDIs were observed on 284 (2.4%) (n = 11 743) prescriptions. The drug pairs with potential drug-drug interactions prescribed most, were imipramine with methylphenidate [43 cases (15.1%)] and valproic acid [38 cases (13.4%)], and followed by methylphenidate in combination with fluoxetine and sertraline [both documenting 32 cases (11.3%), respectively. The TCAs accounted for 182 (64.1%) cases of possible DDIs (drug-drug interactions), whereas combination therapy of SSRIs and TCAs accounted for 21.4% of potential DDIs. In conclusion, this study determined that there were a number of differences with regard to antidepressant prescribing in children and adolescents. Recommendations for future studies were made. / MPharm (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

This study set out to review and analyse aspects of antidepressant prescribing in children and adolescents in a section of the private health care sector of South Africa. The research was conducted in two phases, namely a literature review and an empirical investigation. The aim of the literature review was to provide background to the study by conceptualising antidepressants. The empirical review followed a retrospective, descriptive, observational design. The data employed in the study was obtained from the medicine claims database of a South African Pharmaceutical Benefit Management (PBM) company. The study population consisted of 3 611 children and adolescents receiving ≥1 antidepressants from 1 January 2010 to 31 December 2010. Basic descriptive statistics, such as frequency, prevalence, average, weighted average, standard deviation, weighted standard deviation, median, effect sizes, prescribed daily dosages and DU95% methodology were used to characterise the study sample, and were calculated using the Statistical Analysis System SAS® for Windows 9.3® program. The data were used to determine the prescribing patterns of antidepressants with regard to age, gender, geographic area, type of prescriber, the comparison of prescribed daily dosages vs. recommended daily dosages, and the prevalence of potential drug-drug interactions. Potential drug-drug interactions were identified and compiled by using various interaction compendia, whereas recommended daily dosages were identified by cross-referencing various dosage compendia. The study population consisted of 1 850 girls and 1 761 boys. The mean age of girls was 13.7 ± 3.9 years, vs. 12.3 ± 3.8 years for boys (d = 0.4). A total of 11 735 prescriptions containing 12 272 antidepressants were documented in 2010. Results of the study furthermore showed that the average number of prescriptions claimed per patient increased with age, from an average of 1.0 ± 0.28 among those up to the age of 2 years, to an average of 3.4 ± 3.21 among those 16 to 18 years of age. Prescribing with regard to age groups differed, rising gradually from birth and peaking at middle childhood for boys, whereas antidepressant use in girls increased from birth up to 6 years of age, reaching a plateau and increases again from age 13 and onward. Approximately 25% (n = 12 272) of antidepressants prescribed were either not indicated in children, or the dosages were deemed too high. More than 50% (n = 12 272) of antidepressants prescribed were in the Gauteng province. The SSRIs (selective serotonin re-uptake inhibitors) and the TCAs (tricyclic antidepressants) were the most prescribed antidepressants in both gender groups. The male-to-female ratio for the selective serotonin re-uptake inhibitors was 0.9, compared to 1.2 for the tricyclic antidepressants. The top three antidepressants prescribed were imipramine (21.8%), citalopram (15.3%) and escitalopram (14.7%, n = 12 272). Potential DDIs were observed on 284 (2.4%) (n = 11 743) prescriptions. The drug pairs with potential drug-drug interactions prescribed most, were imipramine with methylphenidate [43 cases (15.1%)] and valproic acid [38 cases (13.4%)], and followed by methylphenidate in combination with fluoxetine and sertraline [both documenting 32 cases (11.3%), respectively. The TCAs accounted for 182 (64.1%) cases of possible DDIs (drug-drug interactions), whereas combination therapy of SSRIs and TCAs accounted for 21.4% of potential DDIs. In conclusion, this study determined that there were a number of differences with regard to antidepressant prescribing in children and adolescents. Recommendations for future studies were made. / MPharm (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

Numerous natural products are widely used as first-line/alternative therapeutics and dietary supplements in both western and eastern society. However, the safety and efficacy profiles for herbal products are still limited. Organic anion transporters (OATs; SLC22 family) are expressed in many barrier organs and mediate in vivo body disposition of a broad array of endogenous substances and clinically important drugs. As some dietary flavonoids and phenolic acids were previously demonstrated to interact with OATs, it is necessary to explore the potential interaction of such components found in natural products in order to avoid potential OAT-mediated drug-drug interactions (DDIs). The inhibitory effects of 23 natural products were assessed on the function of human (h) OATs, hOAT1 (SLC22A6), hOAT3 (SLC22A7), and hOAT4 (SLC22A11) and/or the murine (m) orthologs mOat1 and mOat3. For compounds exhibiting marked inhibition at initial screening, dose-response curves (IC50 values) and DDI indices were determined. At the initial screening concentrations, 14, 19, and 2 test compounds exhibited significant inhibition on hOAT1, hOAT3, and hOAT4, respectively. Additionally, all test Danshen (a Chinese herbal medicine) hydrophilic components significantly reduced mOat1- and mOat3-mediated substrate uptake at 1 mM. For selected compounds, the IC50 and Ki values were estimated to be in the micromolar or even nanomolar range. Considering the clinical plasma concentration and unbound fraction in plasma, DDI indices for gallic acid, gentisic acid, lithospermic acid, protocatechuic acid, rosmarinic acid, salvianolic acid B, and tanshinol indicated DDIs may occur in vivo in situations of co-administration of these compounds and clinical therapeutics known to be OAT substrates. Finally, a new, rapid, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify gallic acid and gentisic acid in cell lysates in order to measure cellular uptake of these compounds in mOat1- or mOat3-expressing cells. Significant cellular uptake of gallic acid was observed in mOat1-expressing cells, compared with background control cells. The absorptive uptake was completely blocked by probenecid (known OAT inhibitor) at 1 mM. These results indicate that gallic acid is a substrate for mOat1 and suggest that human OAT1 might be involved in the active renal secretion of gallic acid.

Introduction: Prostitution is a phenomenon naturally related to different type of risky behavior such as drug use. There is an easier access to psychoactive substances in the sex business environment where becoming drug addict can be more accelerated. Psychoactive substances can be used as a way of breaking moral boundaries while working in sex business. The experts believe that drug use contributes to relaxation and reduces both mental and physical barriers when providing sexual services. Goals: The goal of this dissertation is to look into the issue of prostitution in the Czech Republic in the years 2010 to 2014 to map out the illegal drug use and presence of sexually transmitted diseases within the sex business. Methods: The practical part of this dissertation was based on secondary analysis of data obtained by long term research by the organization Rozkoš bez rizika (Pleasure without Risk) in sex business. The data analysis was taken between the years 2010 and 2014. Results: Sexual services are mostly provided in night clubs by girls and women in the age of 21-30, women of the Czech nationality, single women. The highest level of education is mostly practical school without graduation. The concentration of sex workers in capital Prague and in the border area with Germany and Austria was...

Submitted by admin tede (tede@pucgoias.edu.br) on 2016-12-13T12:04:47Z No. of bitstreams: 1 FABIO PEREIRA ALVES.pdf: 201664 bytes, checksum: 718e7efb9c550a5fe0196ea09029b588 (MD5) / Made available in DSpace on 2016-12-13T12:04:47Z (GMT). No. of bitstreams: 1 FABIO PEREIRA ALVES.pdf: 201664 bytes, checksum: 718e7efb9c550a5fe0196ea09029b588 (MD5) Previous issue date: 2005-10-17 / Based on psychoanalysis, the present work has as its objective to study the family ties between a drug addict and his family. According to DSM-IV, the medical nosography insists on considering drug addiction a disease; however, would that be one of the causes or just the consequence of other pathologies? On the other hand, drug addiction seems to be what some authors call “modernity excesses”. This way, it is regarded as a sign of abuse, of law breaking; that is, it is the absence of reference points, limits, rules. The drugs say what cannot be said (Olievenstein, 1989), they expose the susceptible family ties. They sustain an identification in the emptiness, without a body, they are the sign of what is “missing”. A drug addicted recognizes in the abstinence what is lacking, that is why he dedicates himself completely to this cause that is why drug addiction exists (Rassial, 1999). Through the psychoanalytical listening process, two clinical interviews were held in two different moments: first with the father and later with his addict son. The results show family ties as a “transitional object”; ties that put in evidence the fragile link between father and son. This fragility is the result of the poor identification of the subject with the object, what seems to end up in the son’s fixation on a position of demand, a position between primary narcissism and the entrance in the Oedipus. The results make us suppose that the transitional object’s paradigm is an important theoretical model that enables the understanding and the clinical intervention in cases of drug addiction. / A partir do referencial psicanalítico, buscou-se no presente trabalho estudar como se configura o vínculo em uma família com adolescente toxicômano. Segundo o DSMIV, a nosografia médica insiste em colocar a toxicomania como uma doença; mas seria essa uma causa ou conseqüência de outras patologias? Por outro lado, a toxicomania parece apontar para o que alguns autores chamam de “excessos da modernidade”. Dessa forma, ela funciona como um signo do abuso, da transgressão à Lei; ou seja, é a ausência de referenciais, de limites, de norma. A droga tem a função de dizer o indizível (Olievenstein, 1989) ela denuncia o fio tênue do vínculo familiar. Ela sustenta uma identificação no vazio, sem corpo, ela é a marca da ‘falta’. O sujeito toxicômano reconhece na abstinência o que lhe falta [manque], por isso, encontra-se totalmente envolvido na busca desse objeto, essa é a verdadeira razão de ser da estrutura toxicômana (Rassial, 1999). Dentro do dispositivo de escuta psicanalítica, procedeu-se a duas entrevistas do tipo clínico, realizadas em dois momentos: inicialmente com o pai, e posteriormente com o filho adolescente usuário de droga. O material coletado nas entrevistas aponta para uma configuração no vínculo familiar, que parece tomar a noção de “objeto transicional” como modelo; um vínculo que evidencia uma ligação frágil entre pai e filho. Em que essa fragilidade é resultado de uma identificação precária do sujeito com o objeto, que parece resultar na fixação do filho em uma posição de demanda, uma posição entre narcisismo primário e a entrada no Édipo. Os resultados nos levam a supor que o paradigma do objeto transicional é um importante modelo teórico para a compreensão e a intervenção clínica em casos de toxicomania.

A (-)- grandisina (GRA) é um produto natural da classe das lignanas e é encontrada em muitas espécies de plantas das regiões Norte e Nordeste do Brasil. Por apresentar diversas propriedades biológicas, como atividade tripanocida, anti-inflamatória, antinociceptiva, e principalmente atividade antileucêmica e antitumoral contra tumores de Ehrlich, a GRA pode ser considerada um potencial candidato a fármaco. Porém, para que a GRA se torne um fármaco são necessárias diversas etapas de estudos, incluindo estudos pré-clínicos de interações medicamentosas (DDI). As DDI ocorrem principalmente devido a inibições diretas e tempo-dependentes das enzimas do citocromo P450 (CYP450), uma superfamília de enzimas responsável por metabolizar cerca de 75% dos fármacos em uso. Os estudos pré-clínicos de DDI envolvem o conhecimento do potencial inibitório do candidato a fármaco sobre essas enzimas e esses estudos podem ser realizados empregando diversos modelos in vitro, como, por exemplo, microssomas hepáticos de humanos (HLM). Assim, nesse estudo foi avaliado o efeito inibitório da GRA sobre a atividade das principais isoformas do CYP450 e também foram determinadas as isoformas que contribuem para a formação dos metabólitos da GRA. Os resultados demonstraram que múltiplas isoformas participam da formação dos metabólitos da GRA, com destaque para a CYP2C9, que participa da formação de todos os metabólitos. Em relação aos estudos de inibição, foi possível concluir que a GRA é um inibidor fraco da CYP1A2 e CYP2D6, com valores de IC50 maiores do que 200 µM e 100 µM, respectivamente, e um inibidor moderado e competitivo da CYP2C9, com IC50 igual a 40,85 µM e Ki igual a 50,60 µM. Para a CYP3A4 o potencial inibitório da GRA foi avaliado utilizando dois substratos distintos. A GRA demonstrou ser tanto um inibidor dose-dependente moderado e competitivo dessa isoforma, quanto um inibidor tempo-dependente baseado em mecanismo com potencial de inativação equiparável ao do irinotecano, inibidor baseado em mecanismo clinicamente significativo. Utilizando a nifedipina como substrato os valores de IC50 e Ki foram 78,09 µM e 48,71 µM, respectivamente. Já os valores dos parâmetros cinéticos de inativação foram KI= 6,40 µM, kinact= 0,037 min-1 e Clinact= 5,78 mL min-1 µmol-1. Para os ensaios empregando o midazolam os valores de IC50 e Ki foram 48,87 µM e 31,25 µM, respectivamente, e os valores dos parâmetros cinéticos de inativação foram KI= 31,53 µM, kinact= 0,049 min-1 e Clinact= 1,55 mL min-1 µmol-1. Com relação a CYP2E1, por sua vez, foi possível observar que a GRA tem capacidade de aumentar a atividade dessa isoforma significativamente a partir da concentração de 4 µM. Portanto, conclui-se que não há risco da GRA apresentar interações medicamentosas com fármacos metabolizados pela CYP1A2 e CYP2D6, enquanto que para a CYP2C9, apesar da GRA ser um inibidor moderado dessa isoforma, o risco é baixo. Já para medicamentos metabolizados pela CYP2E1 e CYP3A4 o risco de DDI existe e isso deve ser cuidadosamente monitorado in vivo, principalmente porque a CYP3A4 é a isoforma responsável por catalisar o metabolismo da maioria dos fármacos. / (-)-grandisin (GRA) is a lignanic natural product found in many species of plants from North and Northeast of Brazil. This compound has several biological properties, such as trypanocide, anti-inflammatory, antinociceptive, antileukemia activity and antitumor activity against Ehrlich tumor. Because of these biological properties, GRA is considered a potential drug candidate, however, before becoming a new drug, GRA has to undergo various tests, including preclinical drug-drug interactions (DDI) studies. Most of the times, DDI occur because of direct and time-dependent inhibitions of cytochrome P450 (CYP450) enzymes, an enzyme superfamily responsible for metabolizing the vast majority of drugs administered. Preclinical drug-drug interactions studies involve the evaluation of the potential of a drug candidate to inhibit this superfamily of enzymes and these studies can be conducted using in vitro models, such as human liver microsomes (HLM). Therefore, in this project, the inhibitory effect of GRA on the activity of some CYP450 isoforms was evaluated and the isoforms that catalyze the formation of GRA\'s metabolites were also determined. Results showed that multiple CYP450 isoforms participate in the GRA\'s metabolites formation, highlighting CYP2C9, which catalyzes the formation of all metabolites. The inhibition studies showed that GRA is a weak inhibitor of CYP1A2 and CYP2D6, with IC50 values greater than 200 µM and 100 µM, respectively, and a moderate and competitive inhibitor of CYP2C9, with IC50 value equal to 40.85 µM and Ki value equal to 50.60 µM. The capability of GRA to inhibit CYP3A4 was evaluated using two different substrates. GRA showed to be a moderate and competitive dose- dependent inhibitor of this isoform and also a mechanism-based time-dependent inhibitor with potential of inactivation comparable to irinotecan, a clinically significant mechanism-based inhibitor. IC50 and Ki values obtained using nifedipine as substrate were 78.09 µM and 48.71 µM, respectively, and inactivation kinetics parameters were KI= 6.40 µM, kinact= 0,037 min-1 e Clinact= 5.78 mL min-1 µmol-1. On the other hand, IC50 and Ki values using midazolam as substrate were 48.87 µM and 31.25 µM, respectively, and the values of inactivation kinetics parameters were KI= 31.53 µM, kinact= 0,049 min-1 and Clinact= 1.55 mL min-1 µmol-1. With respect to CYP2E1, it was observed that GRA increases its activity significantly from a concentration of 4 µM. Therefore, it is possible to conclude that there is no risk of DDI between GRA and drugs metabolized by CYP1A2 and CYP2D6, while for CYP2C9, although GRA is a moderate inhibitor of this isoform, the risk is low. Finally, for drugs metabolized by CYP3A4 and CYP2E1 there is risk of DDI and this should be carefully monitored in humans, mainly because CYP3A4 is an isoform responsible for catalyzing the metabolism of most drugs in use.

Le rein joue un rôle essentiel dans l’élimination des médicaments et de leurs métabolites, de ce fait il assure la défense de l'organisme contre de potentiels xénobiotiques toxiques. Particulièrement, les transporteurs des tubules proximaux rénaux qui ont un rôle dans la sécrétion tubulaire des médicaments. Ainsi, ils sont des déterminants important de la biodisponibilité des xénobiotiques dans l’organisme.Dans cette thèse nous nous sommes intéressés à l’implication des transporteurs rénaux humains hOAT1 et hOAT3 dans des interactions médicamenteuses moyennant des modèles in vitro. Après construction et validation des modèles d’études cellulaires HEK-hOAT1 et HEK-hOAT3, nous avons testé l’effet des inhibiteurs de la pompe à protons sur le transport du méthotrexate par les OATs ainsi que l’effet des antiviraux sur l’influx du tenofovir par ces mêmes transporteurs. Grâce à nos modèles cellulaires nous avons tenté d’expliquer in vitro de probables interactions médicamenteuses décrites en clinique. / The kidney plays an essential role in the elimination of drugs and their metabolites, thus it ensures the defense of the body against potential toxic xenobiotic. Particularly, the secretory transporters in the proximal tubule are major determinants of the disposition of xenobiotic in the body.In this thesis we investigated the involvement of human organic anions transporters hOAT1 and hOAT3 in drug drug interactions through study on in vitro cell models. After construction and validation of cells models studies HEK-hOAT1 and HEK-hOAT3, we tested the effect of proton pump inhibitors on methotrexate transport by OATs and the effect of antivirals on the influx of tenofovir by these two transporters. With our models we tried to explain in vitro probable drug interactions described in the clinic.