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| Hauptseite > Publikationsdatenbank > Influence of incubation conditions on microsomal metabolism of xanthine-derived A1 adenosine receptor ligands > print |
| Hauptseite > Publikationsdatenbank > Influence of incubation conditions on microsomal metabolism of xanthine-derived A1 adenosine receptor ligands > print |
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| 100 | 1 | _ | |a Schneider, Daniela |0 P:(DE-Juel1)156407 |b 0 |e Corresponding author |u fzj |
| 245 | _ | _ | |a Influence of incubation conditions on microsomal metabolism of xanthine-derived A1 adenosine receptor ligands |
| 260 | _ | _ | |a New York, NY [u.a.] |c 2019 |b Elsevier |
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| 520 | _ | _ | |a Introduction:In vitro metabolism models such as liver microsomes represent an important tool for the development of novel radioligands.Comparability and physiological relevance of invitro metabolism data criticallydepend on the careful evaluation and optimization of assay protocols. We therefore investigated the influence ofincubation conditions on the microsomal stability of xanthine-derived A1 adenosine receptor (A 1AR) ligandswhich have been developed for positron emission tomography (PET).Methods:Substrate depletion assays using rat liver microsomes (RLM) were performed for three analogouscompounds which differ with regard to the metabolically vulnerable substituent at the xanthine C8 position.Incubation conditionswerevariedsystematically. Additionally, the stability of the cofactor NADPH duringing cubation was investigated.Results:Microsomal metabolism was strongly influenced by buffer pH, organic solvents and preincubation time.Substrate depletion values varied up to5-fold depending on incubation matrix composition, however, the rankorder of metabolic stability remained unchanged. Prolonged incubation periods led to drastic loss in enzymeactivity which could not be prevented by addition of metal chelators or antioxidants. Cofactor NADPH wasrapidlyoxidizedinmicrosomalmatrix,evenintheabsenceofcytochromeP450substrates.Discussion:Insummary,short incubation times, precise pH control and minimal concentrations of organic solvents are mandatory to obtain reliable microsomal stability data. Furthermore, invitro metabolic stability of thetested A 1 AR ligands varied largely depending on the particular C8 substituent. Consequently, structural modifications at the xanthine C8 position appear to be a promising strategy for the improvement of A1AR PETradioligands |
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