title: Metabolic switching of BILR 355 in the presence of ritonavir. II. Uncovering novel contributions by gut bacteria and aldehyde oxidase.
abstract: Ritonavir (RTV) was used as a boosting agent to increase the clinical exposure of 11-ethyl-5,11-dihydro-5-methyl-8-[2-[(1-oxido-4-quinolinyl)oxy]ethyl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (BILR 355), an inhibitor of the human immunodeficiency virus, by inhibiting the CYP3A-mediated metabolism of BILR 355. However, although the levels of BILR 355 increased upon concomitant administration of RTV, a metabolite of BILR 355, BILR 516, which was not detected previously in humans dosed with BILR 355 alone, became a disproportionate human metabolite with levels exceeding the parent levels at steady state. This was an unusual finding based on the in vitro and in vivo metabolic profiles of BILR 355 available at that time. Our studies reveal that BILR 355 is reduced to an intermediate, BILR 402, by gut bacteria and the reduced metabolite (BILR 402) is then oxidized by aldehyde oxidase to form BILR 516, the disproportionate human metabolite. The role of aldehyde oxidase helped to explain the somewhat unique formation of BILR 516 in humans compared with preclinical animal species. This article underlines the increasing importance of two individually atypical enzymes in drug development, gut bacterial biotransformation and aldehyde oxidase, which in combination provided a unique metabolic pathway. In addition, this article clearly elucidates an example of novel metabolic switching and, it is hoped, raises awareness of the potential for metabolic switching in combination drug therapies.
authors.affiliation: Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd., Ridgefield, CT 06877, USA. yongmei.li@boehringer-ingelheim.com
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: W George
authors.initials: WG
authors.lastname: Lai
authors.forename: Andrea
authors.initials: A
authors.lastname: Whitcher-Johnstone
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Tweedie
mesh_terms: D042931:Aldehyde Oxidase / Q000378:metabolism*; D001381:Azepines / Q000378:metabolism*; D001419:Bacteria / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D005243:Feces; D041981:Gastrointestinal Tract / Q000201:enzymology / Q000378:metabolism* / Q000382:microbiology*; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008862:Microsomes, Liver / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D019438:Ritonavir / Q000378:metabolism*
chemical_list: C548654:5,11-dihydro-11-ethyl-5-methyl-8-(2-(1-oxido-4-quinolinyl)ethyl)-6H-dipyrido(3,2-B,2',3'-E)(1,4)diazepin-6-one; D001381:Azepines; D011725:Pyridines; D042931:Aldehyde Oxidase; D012194:RNA-Directed DNA Polymerase; D019438:Ritonavir