Mechanistic in vitro studies indicate that the clinical drug –drug interactions between protease inhibitors and rosuvastatin are driven by inhibition of intestinal BCRP and hepatic OATP1B1 with minimal contribution from OATP1B3, NTCP and OAT3

This work sought to clarify the mechanisms underlying clinical DDIs between rosuvastatin and protease inhibitors. Investigating in vitro inhibition of the critical transporter disposition pathways of rosuvastatin, and subsequent incorporation of cell test system derived determined Ki values into mechanistic static equations, enabled successful quantitative prediction of clinical AUCRs. Predictions suggest the mechanisms driving DDI are principally inhibition of intestinal BCRP and hepatic OATP1B1, with minimal contribution from OATP1B3, NTCP or OAT3. AbstractPrevious use of a mechanistic static model to accurately quantify the increased rosuvastatin exposure due to drug –drug interaction (DDI) with coadministered atazanavir underpredicted the magnitude of area under the plasma concentration–time curve ratio (AUCR) based on inhibition of breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1. To reconcile the disconnect bet ween predicted and clinical AUCR, atazanavir and other protease inhibitors (darunavir, lopinavir and ritonavir) were evaluated as inhibitors of BCRP, OATP1B1, OATP1B3, sodium taurocholate cotransporting polypeptide (NTCP) and organic anion transporter (OAT) 3. None of the drugs inhibited OAT3, nor d id darunavir and ritonavir inhibit OATP1B3 or NTCP. All drugs inhibited BCRP-mediated estrone 3-sulfate transport or OATP1B1-mediated estradiol 17β-D-glucuronide transport with the same rank order of inhibitory potency...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research