title: Characterization of the transmembrane transport and absolute bioavailability of the HCV protease inhibitor danoprevir.
abstract: OBJECTIVE
  Understanding transmembrane transport provides a more complete understanding of the pharmacokinetics of a drug and mechanistic explanations for drug-drug interactions. Here, the transmembrane transport of danoprevir (hepatitis C virus protease inhibitor) and the effects of ritonavir and ciclosporin on transmembrane transport of danoprevir were evaluated and clinical pharmacokinetic studies of danoprevir co-administered with/without ritonavir and ciclosporin were conducted.
  
  
  METHODS
  Transcellular transport of danoprevir was evaluated in Lewis lung cancer porcine kidney, Madin-Darby canine kidney, or Chinese hamster ovary cells transfected with human transport proteins, and in human hepatocytes. The pharmacokinetics of intravenous and oral danoprevir administered with/without ritonavir, and the impact of ciclosporin on danoprevir pharmacokinetics were evaluated in randomized, open-label, crossover studies in healthy subjects.
  
  
  RESULTS
  Danoprevir transport in vitro involved organic anion transporting polypeptide (OATP) 1B1, OATP1B3, P-glycoprotein, and multidrug resistance protein-2, but not breast cancer resistance protein. Ritonavir and ciclosporin inhibited transport of danoprevir by human hepatocytes. The pharmacokinetics of intravenous danoprevir 6 mg were not altered by oral ritonavir 100 mg. In contrast, exposure to oral danoprevir 100 mg increased two- to threefold when co-administered with ritonavir. Absolute bioavailability of danoprevir 100 mg was low (1.15%), but increased more than threefold (3.86%) when co-administered with ritonavir. Oral ciclosporin 100 mg increased exposure to intravenous danoprevir 2 mg and oral ritonavir 100 mg.
  
  
  CONCLUSIONS
  Collectively, these studies provide insight into the transmembrane transport and pharmacokinetics of danoprevir and the mechanisms that underlie a recently reported, three-way drug-drug interaction involving danoprevir, ritonavir, and ciclosporin.
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ, USA, barbara.brennan@roche.com.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: Agnès
authors.initials: A
authors.lastname: Poirier
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moreira
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.forename: Petra
authors.initials: P
authors.lastname: Goelzer
authors.forename: Renée
authors.initials: R
authors.lastname: Portmann
authors.forename: Jiney
authors.initials: J
authors.lastname: Asthappan
authors.forename: Christoph
authors.initials: C
authors.lastname: Funk
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D016466:CHO Cells; D018827:Carcinoma, Lewis Lung / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018592:Cross-Over Studies; D003521:Cyclopropanes; D016572:Cyclosporine / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000493:pharmacokinetics* / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D016032:Randomized Controlled Trials as Topic; D019438:Ritonavir / Q000494:pharmacology; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000494:pharmacology; D013552:Swine; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D026901:Membrane Transport Proteins; D011480:Protease Inhibitors; D013449:Sulfonamides; D016572:Cyclosporine; C553752:danoprevir; D011392:Proline; D019438:Ritonavir