title: Enzyme-transporter interplay in the formation and clearance of abundant metabolites of faldaprevir found in excreta but not in circulation.
abstract: Faldaprevir is a hepatitis C virus protease inhibitor that effectively reduces viral load in patients. Since faldaprevir exhibits slow metabolism in vitro and low clearance in vivo, metabolism was expected to be a minor clearance pathway. The human [(14)C] absorption, distribution, metabolism, and excretion study revealed that two monohydroxylated metabolites (M2a and M2b) were the most abundant excretory metabolites in feces, constituting 41% of the total administered dose. To deconvolute the formation and disposition of M2a and M2b in humans and determine why the minor change in structure [the addition of 16 atomic mass units (amu)] produced chemical entities that were excreted and were not present in the circulation, multiple in vitro test systems were used. The results from these in vitro studies clarified the formation and clearance of M2a and M2b. Faldaprevir is metabolized primarily in the liver by CYP3A4/5 to form M2a and M2b, which are also substrates of efflux transporters (P-glycoprotein and breast cancer resistance protein). The role of transporters is considered important for M2a and M2b as they demonstrate low permeability. It is proposed that both metabolites are efficiently excreted via bile into feces and do not enter the systemic circulation to an appreciable extent. If these metabolites permeate to blood, they can be readily taken up into hepatocytes from the circulation by uptake transporters (likely organic anion transporting polypeptides). These results highlight the critical role of drug-metabolizing enzymes and multiple transporters in the process of the formation and clearance of faldaprevir metabolites. Faldaprevir metabolism also provides an interesting case study for metabolites that are exclusively excreted in feces but are of clinical relevance.
authors.affiliation: Drug Metabolism & Pharmacokinetics (Y.L., J.Z., D.R., M.E.T., D.O., J.X., D.J.T.), Chemical Development (C.A.B.), and Analytical Development (N.G.), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.forename: Diane
authors.initials: D
authors.lastname: Ramsden
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Taub
authors.forename: Drané
authors.initials: D
authors.lastname: O'Brien
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Carl A
authors.initials: CA
authors.lastname: Busacca
authors.forename: Nina
authors.initials: N
authors.lastname: Gonnella
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tweedie
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000097:blood / Q000378:metabolism; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004355:Drug Stability; D004356:Drug Storage; D005243:Feces / Q000737:chemistry / Q000201:enzymology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008657:Metabolic Clearance Rate; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009842:Oligopeptides / Q000097:blood / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives; D011485:Protein Binding; D011804:Quinolines; D013844:Thiazoles / Q000097:blood / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D009842:Oligopeptides; D011804:Quinolines; D013844:Thiazoles; D003577:Cytochrome P-450 Enzyme System; C552340:faldaprevir; D011392:Proline; D007930:Leucine