Species differences in liver accumulation and metabolism
In the attempt to find the most suitable pharmacokinetic (PK) model to project human liver tissue levels for future nucleotide prodrugs, authors re-evaluated the following models in in vitro and in vivo setting:
- Mouse models (C57BL/6 and/or FVB);
- PXB-mouse® (cDNA-uPA/scid mouse with highly humanized liver);
- Rat model (Sprague-Dawley rat);
- Hamster (Golden Syrian hamster);
- Dog (Beagle dog);
- Monkey (Cynomolgus monkey)
Liver accumulation of triphosphate was investigated after oral administration of sofosbuvir. The intestinal absorption, which may be affected by species differences in efflux transport, is followed by exposure to plasma in portal vein and distribution into the liver. Uptake of the drug is anticipated to happen by passive diffusion, as this nucleotide prodrug is not a substrate for hepatic uptake transporters.