Experimental investigation and modelling of pH profiles for effective membrane permeability of drug substances
Date
2019-07-09
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Abstract
Enamik ravimeid manustatakse suukaudselt, näiteks tabletid, kapslid ja lahused. Ravimi toimeainete (raviainete) arendamisel on oluline arvestada seedetraktis toimuvaid protsesse, seedetrakti ehitust ja omadusi eri piirkondades. Üks selline varieeruv omadus on pH, mis muutub väga happelisest (maos) kuni aluseliseni (pärasooles), ja sõltub sellest, kas hiljuti on toitutud või on mõnda aega paastutud. Seedetrakti pH mõjutab raviaine omadusi ja seeläbi määrab tingimused mille juures ning millises seedetrakti piirkonnas saab raviaine liikuda vereringesse. Sellised teadmised on olulised juba raviainete kandidaatide valimisel ravimiarenduse varajases etapis ja aitavad vähendada uute raviainete ebaõnnestumist mõnes hilisemas ravimiarenduse etapis.
Käesolev doktoritöö keskendus sellele, kuidas pH mõjutab raviainete membraaniläbitavust, ja uute teadmiste saamiseks kasutati nii eksperimentaalseid kui ka arvutuslikke keemiainformaatika meetodeid. Doktoritöös uuriti läbitavust tehislikus membraanis, mis jäljendab seedetrakti ja vereringe vahelist barjääri. Töö käigus mõõdeti ja koostati laiaulatuslik ja süstemaatiline andmebaas raviainete membraaniläbitavustest eri pH väärtuste juures. Membraaniläbitavuse ja inimese soolestikus toimuva imendumise võrdlus näitas, et võttes arvesse pH-sid happelisest kuni aluseliseni võimaldab täpsemalt hinnata läbitavust seedetraktis.
Koostatud andmebaas võimaldas luua keemiainformaatika arvutusmudeleid, mis prognoosivad raviaine membraaniläbitavust molekuli struktuurist. Doktoritöö käigus tuletati üldised ja keemiliste ühendite klassidele vastavad prognoosmudelid. Neid saab rakendada membraaniläbitavuse hindamiseks nii numbriliselt kui ka klassipõhiselt eri pH-del (raviainete pH-läbitavuse profiil), kuid ka üle kogu seedetrakti pH vahemiku. Need mudelid võimaldavad uurida huvipakkuvaid suukaudselt manustatavaid raviainete kandidaate, mida pole veel sünteesitud, ja mida seetõttu ei saa uurida eksperimentaalselt. Eksperimentaalsete andmete võrdlusest saadud teadmisi ja välja töötatud keemiainformaatika arvutusmudeleid saab rakendada ka toiduaine-, kosmeetika- ja keemiatööstuses, et tuvastada keemiliste ühendite mõju inimesele ilma loomkatseteta.
Most drugs are administered orally, like tablets, capsules, and solutions. When developing the drug substances, it is important to consider the processes in the gastrointestinal tract, and the structure and properties in different sections of the gastrointestinal tract. One such property is the pH that changes from very acidic (stomach) to basic (colon) and depends on whether it has been recently fed or fasted for some time. The pH of the gastrointestinal tract affects the properties of the drug substances and thereby determines at what conditions and in what part of the gastrointestinal tract the drug substance can move into the blood circulation. Such knowledge is already important in the selection of drug substance candidates at an early stage of drug discovery and helps to reduce attrition of drug substances in later stages of drug discovery. This thesis focused on how pH influences membrane permeability of drug substances and used both experimental and cheminformatics methods to obtain new knowledge. The doctoral thesis studied membrane permeability in an artificial membrane that mimics the barrier between the gastrointestinal tract and the blood circulation. The study measured and compiled a comprehensive and systematic database of membrane permeability of drug substances at different pH values. Comparison of membrane permeability and human intestinal absorption showed that considering the pH from acidic to basic allows a more accurate evaluation of the permeability in the gastrointestinal tract. The compiled database enabled to develop cheminformatics models to predict the membrane permeability of drug substances from molecular structure. In the course of thesis, general and chemical classes models were derived. They can be applied to evaluate membrane permeability, both numerically and based on class, at different pH-s (pH-permeability profiles of drug substance), but also across the pH range in the gastrointestinal tract. These models allow the examination of orally administered drug substance candidates, which have not yet been synthesised and therefore cannot be investigated experimentally. The knowledge gained from the comparison of experimental data and the developed cheminformatics models can also be applied in the food, cosmetic, and chemistry industries to detect the effects of chemicals on humans without animal testing.
Most drugs are administered orally, like tablets, capsules, and solutions. When developing the drug substances, it is important to consider the processes in the gastrointestinal tract, and the structure and properties in different sections of the gastrointestinal tract. One such property is the pH that changes from very acidic (stomach) to basic (colon) and depends on whether it has been recently fed or fasted for some time. The pH of the gastrointestinal tract affects the properties of the drug substances and thereby determines at what conditions and in what part of the gastrointestinal tract the drug substance can move into the blood circulation. Such knowledge is already important in the selection of drug substance candidates at an early stage of drug discovery and helps to reduce attrition of drug substances in later stages of drug discovery. This thesis focused on how pH influences membrane permeability of drug substances and used both experimental and cheminformatics methods to obtain new knowledge. The doctoral thesis studied membrane permeability in an artificial membrane that mimics the barrier between the gastrointestinal tract and the blood circulation. The study measured and compiled a comprehensive and systematic database of membrane permeability of drug substances at different pH values. Comparison of membrane permeability and human intestinal absorption showed that considering the pH from acidic to basic allows a more accurate evaluation of the permeability in the gastrointestinal tract. The compiled database enabled to develop cheminformatics models to predict the membrane permeability of drug substances from molecular structure. In the course of thesis, general and chemical classes models were derived. They can be applied to evaluate membrane permeability, both numerically and based on class, at different pH-s (pH-permeability profiles of drug substance), but also across the pH range in the gastrointestinal tract. These models allow the examination of orally administered drug substance candidates, which have not yet been synthesised and therefore cannot be investigated experimentally. The knowledge gained from the comparison of experimental data and the developed cheminformatics models can also be applied in the food, cosmetic, and chemistry industries to detect the effects of chemicals on humans without animal testing.
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Keywords
ravimid, toimeained, soolepermeaablus, pH, tehismembraanid, permeaablus, kvantitatiivne struktuur-aktiivsus sõltuvus, prognoosmudelid, ravimiarendus