Karaciğerdeki İlaç Dispozisyonu Üzerine Rifampisinin Etkisinin İncelenmesi ve Farmakokinetik Modelleme

Transporter-mediated pharmacokinetics is one of the determinants in hepatic drug disposition and drug-drug interactions. Among several influx (uptake) transporters expressed in the membranes of hepatocytes, hepatic organic anion-transporting polypeptides (OATPs) are clinically important major transporters to be evaluated during drug development. The aim of this thesis was to investigate the hepatic disposition of pitavastatin in the absence and presence of an OATP/Oatp inhibitor rifampicin using in situ isolated perfused rat liver method with monitoring coproporphyrin I and coproporphyrin III as endogenous biomarkers. The samples were collected from perfusate, liver tissue and bile, and analysed by validated bioanalytical methods. Hepatic and biliary clearances plus hepatic bioavailability of pitavastatin were estimated using model independent analysis. Reasonable correlations between pitavastatin and endogenous biomarkers in the liver and bile were obtained. A mechanistic compartment model composed of perfusate, liver extracellular and intracellular, and bile compartments was developed to simulate hepatobiliary distribution and estimate hepatic uptake and biliary clearances of pitavastatin by simultaneous fitting of the data obtained in two conditions (with and without rifampicin). The current dynamic model, which excludes any extrahepatic variable, delivers a refined clearance estimation to characterize the disposition of pitavastatin in the rat liver.Taşıyıcı aracılı farmakokinetik hepatik ilaç dispozisyonu ve ilaç-ilaç etkileşimleri için önemli belirleyici mekanizmalardan biridir. Hepatosit membranlarında yer alan çeşitli influx taşıyıcılar arasında hepatik organik anyon taşıyıcı polipeptidler (OATP’ler) ilaç geliştirme sürecinde değerlendirilmesi gereken ve klinik olarak önemli ana taşıyıcılardır. Bu tezin amacı in situ sıçan karaciğer perfüzyonu yöntemi kullanarak OATP/Oatp inhibitörü rifampisin varlığında ve yokluğunda pitavastatinin hepatik dispozisyonunun incelenmesi ve endojen biyobelirteçler olan koproporfirin I ve koproporfirin III’ün izlenmesidir. Perfüzat, karaciğer dokusu ve safradan toplanan örnekler valide edilmiş biyoanalitik yöntemler ile analiz edilmiştir. Pitavastatinin hepatik ve safra klerensleri ile hepatik biyoyararlanımı modelden bağımsız yöntem kullanarak tayin edilmiştir. Karaciğer ve safrada pitavastatin ve endojen biyobelirteçler arasında kabul edilebilir bir korelasyon bulunmuştur. Pitavastatinin hepatobiliyer dağılımını simüle etmek ve iki koşulda (rifampisin varlığında ve yokluğunda) elde edilmiş verilerin eş zamanlı analizi ile pitavastatinin hepatik alım ve safra klerenslerini tayin etmek için perfüzat, karaciğer ekstraselüler, karaciğer intraselüler ve safra kompartmanlarından oluşan bir mekanistik kompartman modeli geliştirilmiştir. Karaciğer dışı değişkenlerin dahil edilmediği mevcut dinamik model, pitavastatinin sıçan karaciğerindeki dispozisyonunun karakterize edilmesinde iyileştirilmiş klerens kestirimleri sunmaktadır

Effect Of Particle Size And Surfactant On The Solubility, Permeability And Dissolution Characteristics Of Deferasirox

Deferasirox is an oral iron chelator used for the treatment of chronic iron overload in blood transfusions. Deferasirox is a BCS Class II drug with low solubility and high permeability. In the formulation development stage for BCS Class II compounds, one of the main approaches is solubility enhancement to achieve better dissolution profiles, increased bioavailability and in some cases, dose reduction. The aim of the study was to investigate the effect of particle size and surfactant on the solubility, permeability and dissolution characteristics of deferasirox. Ball milling method was used to reduce the particle size of deferasirox. Pluronic F127 or sodium lauril sulfate (SLS) were selected as surfactants at different concentrations. The maximum increase in the solubility was obtained with 10% SLS at pH 1.2 (from 0.9 mu g/mL to 333.7 mu g/mL), and with 5% Pluronic F127 at pH 6.8 (from 46.8 mu g/mL to 334.2 mu g/mL). Dissolution studies revealed that time to dissolve 85% of deferasirox was decreased as a function of ball milling time and particle size. Permeability studies showed that, in 100 mu M concentration, deferasirox permeability was significantly enhanced by all concentrations of SLS (p0.05). All these results clearly demonstrated that surfactant addition to the formulations was effective for solubility enhancement of deferasirox, and surfactant type in optimized concentrations was very crucial. Particle size reduction can be used as a promising approach to improve dissolution, and hence bioavailability of deferasirox.WoSScopu

Evaluation of preparation methods for orally disintegrating tablets

Oral disintegrating tablets (ODT) are orally administered solid dosage forms commonly used in pediatric and geriatric patients with difficulty in swallowing. The lack of need for water during the use of ODTs is another advantage that increases patient compliance. Many methods are used for the production of ODTs such as direct compression (DC), freeze-drying (FD), spray drying, 3-D printing, melt granulation, phase transition process, molding, sublimation, mass extrusion, cotton candy process. Since the ODTs produced are aimed to disintegrate and dissolve rapidly, and consequently act quickly, the production method parameters need to be optimized in line with the critical product parameters. In this study, the most widely used manufacturing methods (especially DC and FD) for ODT and in vitro quality control tests of ODT are evaluated. [Med-Science 2020; 9(1.000): 265-9