April 2016

XenoTech Scientists Publish Paper, Present Research Evaluating Ketoconazole and its Alternative Clinical CYP3A4-5 Inhibitors as Inhibitors of Drug Transporters

Author:  Michael Millhollen
Posted:  25 April 2016

Sekisui XenoTech scientists published a paper in Drug Metabolism and Disposition evaluating Ketoconazole and its alternative clinical CYP3A4-5 inhibitors as inhibitors of drug transporters, and presented their research at a meeting of the Delaware Valley Drug Metabolism Discussion Group (DVDMDG) earlier this year, during a webinar earlier this month, and with a poster at this month's AAPS/ITC Workshop on Drug Transporters. The paper, authored by Lydia M.M. Vermeer, Caleb D. Isringhausen, Brian W. Ogilvie, and David B. Buckley, is available here

Ketoconazole is known to be a strong CYP3A4/5 inhibitor, and until recently, was utilized in this role in clinical drug-drug interaction (DDI) studies. Unfortunately, ketoconazole has also demonstrated the ability to cause sporadic liver injury or adrenal insufficiency. Due to this, the FDA and EMA recently recommended the suspension of ketoconazole use in DDI studies and suggested the use of alternatives such as itraconazole or clarithromycin. While the effect on CYP3A4/5 function by these compounds is well established, the known effect on drug transporters is limited. The purpose of this study was to determine the inhibitory effects of ketoconazole, clarithromycin, ritonavir, itraconazole (and the itraconazole metabolites hydroxy-, keto-, andN-desalkyl-itraconazole) towards the drug transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, P-gp, BCRP, MRP2, MRP3, and BSEP.

During the webinar, which was presented by Lydia Vermeer, Ph.D., Senior Scientist of Drug Transport at Sekisui XenoTech, key concepts were discussed, including Ketoconazole's use and background, assay methodology and design, the inhibitory effects of ketoconazole and alternative compounds on drug transporters, calculated IC50 values, determination of potential for clinical DDI, and potential limitations of the study. The slides and a recording of the webinar are available here.

The corresponding poster, which was presented by Dr. Vermeer at the April AAPS/ITC Workshop on Drug Transporters in ADME and later updated at the Marbach Castle Drug-Drug Interaction Workshop held from May 29th to June 1st in Germany, is available here.

Learn more about Sekisui XenoTech's Drug Transport Services.

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