title: Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it's not just about OATP1B1.
abstract: The use of statins is widespread across disease areas because many patients have comorbidities. Given that these drugs have become common as comedications, it is essential to have an understanding of the potential risks of drug-drug interactions (DDIs) between statins and candidate drugs in development. Although the hepatic uptake transporter organic anion-transporting polypeptide 1B1 (OATP1B1) is known to play a substantial role in statin-related DDI risk, other transporters and metabolizing enzymes can also be involved. Consequently, a holistic approach to risk assessment is required, tailored to each statin. Using evidence from pharmacogenetics, DDIs, and literature on absorption, distribution, metabolism, and elimination (ADME) in humans, this review identifies pathways that contribute the most to, and are therefore the most critical to, the disposition of each statin. It also provides an understanding of the expected theoretical maximum increase in systemic exposure if the disposition of a statin is inhibited. Finally, on a statin-by-statin basis, we propose in vitro inhibition studies that should be routinely conducted during drug development so as to better assess DDI risk.
authors.affiliation: Global DMPK-In Vitro/In Silico ADME, AstraZeneca R&D Alderley Park, Cheshire, UK. Robert.Elsby@astrazeneca.com
authors.forename: R
authors.initials: R
authors.lastname: Elsby
authors.forename: C
authors.initials: C
authors.lastname: Hilgendorf
authors.forename: K
authors.initials: K
authors.lastname: Fenner
mesh_terms: D000818:Animals; D001692:Biological Transport; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000378:metabolism*; D018570:Risk Assessment; D014018:Tissue Distribution
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human