Summary
Samenvatting non-cilnical drug development
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Dit is een korte samenvatting over het deel non-cilnical drug development
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Non-clinical DD (Annaert)ADME testing (vroege ontwikkeling)
Absorptie
o Caco 2 (cancer colon cellen)
Vormen laag Papp meten voorspelling fa (geabsorbeerde fractie)
voorspelling F (biologische beschikbaarheid)
Oppervlakte, concentratie en snelheid gekend Papp flux
Flux: Papp (afh van log P) * initiële concentratie (afh van oplosbaarheid)
1 celtype
Geen mucuslaag
Brengen ook transporters (bv. Pgp) tot expressie beter dan enkel log P ook
polariteit van transport bekijken F voorspellen
o Oplosbaarheid in biorelevante media
Distributie
Metabolisme
o Cl prediction (microsomes, hepatocytes)
Microsomen (microsomal stability screening)
Vd gekend, K uit experiment niet-renale klaring
Screening voor CYP/UGT metabolism
Eliminatiesnelheid verandert continu naarmate dat er minder is
begint het trager te gaan verval is exponentieel
Geen bijdrage cytosolische enzymen en andere cellulaire processen bv.
transporters
Hepatocyten (suspensie of cultuur)
Klaring obv AUC
Veel interindividuele variabiliteit (humaan) gepoold
Beperkte functionaliteit/viabiliteit na cryopreservatie + duur
Corrigeren voor dynamische wisselwerking tussen serum en
hepatocyten biorelevantie ↑
In vivo Cl prediction
Obv in vitro experimenten (IVIVE)
Normaliseren voor mg proteïne (microsomen) of voor #cellen
(hepatocyten)
Rekening houden met hepatic blood flow, protein binding (well-stirred
model)
o Impact of (hepatic) transporters
Veel transporters (bv. Pgp)
Oil-spin methode om opname in hepatocyten (enkel cellen) te bepalen
Activiteit is belangrijk om te meten, mRNA komt hier niet altijd mee overeen
Ontogeny = ontwikkeling van activiteit van een transporter
HIV protease inhibitors
o DDI (CYP inhibition, induction)
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