New strategies to address drug-drug interactions involving OATPs.
Pharmacokinetic drug-drug interactions (DDIs) are a major concern in drug development. Drug transport, along with drug metabolism via cytochrome P450s (CYPs), is increasingly being considered as an integral part of the overall pharnmacokinetics profile of a drug. Inhibition of transporters can lead to altered pharmacokinetics, potentially interfering with drug safety and efficacy. There is an increasing number of DDIs observed with statins, which are widely used in combination therapies, and this can be partly attributed to inhibition of individual hepatic transporters. Studies of these inhibitory interactions in vitro has indicated the importance of both hepatic solute carriers of the organic anion transporting polypeptide (OATP) superfamily and CYP inhibition. Mathematical models have been developed to gain more quantitative insights into the interplay between transport and metabolism of drugs. This article reviews new developments in the area of in vitro tools and modeling approaches that are used to study DDIs related to OATP transporters, with a focus on the clinical relevance of the transport-mediated DDIs involving statins.
Poirier
Agnés
A
Non-Clinical Development - Drug Safety, F Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
Funk
Christoph
C
Lavé
Thierry
T
Noé
Johannes
J
D000818:Animals; D016572:Cyclosporine / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D008962:Models, Theoretical; D027361:Organic Anion Transporters / Q000378:metabolism*; D012293:Rifampin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D013678:Technology, Pharmaceutical / Q000379:methods*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin