title: In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid.
abstract: Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxy-efavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxy-efavirenz (7OH-EFV). So far, most metabolite profile analyses have been restricted to 8OH-EFV, 7OH-EFV, and EFV-N-glucuronide, even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolite profile analysis by tandem mass spectrometry of plasma, cerebrospinal fluid (CSF), and urine samples in 71 human immunodeficiency virus patients taking efavirenz, prior to and after enzymatic (glucuronidase and sulfatase) hydrolysis. We have shown that phase II metabolites constitute the major part of the known circulating efavirenz species in humans. The 8OH-EFV-glucuronide (gln) and 8OH-EFV-sulfate (identified for the first time) in humans were found to be 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6, and CYP3A metabolic pathways, 8OH-EFV/EFV ratios in plasma were an index of CYP2B6 phenotypic activity (P < 0.0001), which was also reflected by phase II metabolites 8OH-EFV-glucuronide/EFV and 8OH-EFV-sulfate/EFV ratios. Neither EFV nor 8OH-EFV, nor any other considered metabolites in plasma were associated with an increased risk of central nervous system (CNS) toxicity. In CSF, 8OH-EFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV-gln, 8OH-EFV-sulfate, and 7OH-EFV-gln were present in CSF at 2- to 9-fold higher concentrations than 8OH-EFV. The potential contribution of known and previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz needs to be further examined in larger cohort studies.
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Manel
authors.initials: M
authors.lastname: Aouri
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Catalina
authors.initials: C
authors.lastname: Barcelo
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Béatrice
authors.initials: B
authors.lastname: Ternon
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Alexia
authors.initials: A
authors.lastname: Anagnostopoulos
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Sabine
authors.initials: S
authors.lastname: Yerly
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Henry
authors.initials: H
authors.lastname: Hugues
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Pietro
authors.initials: P
authors.lastname: Vernazza
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.).
authors.forename: Margalida
authors.initials: M
authors.lastname: Rotger
authors.affiliation: Laboratory of Clinical Pharmacology, Service of Biomedicine (M.A., B.T., M.R., L.A.D.), Division of Clinical Pharmacology, Service of Biomedicine (M.A., C.B., T.B.), Service of Infectious Diseases (B.T., M.C.), Institute of Microbiology (A.T., M.R.), and Innovation and Development, Service of Biomedicine (H.H.), University Hospital and University of Lausanne, Lausanne, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland (A.A., H.F.G.); Institute of Medical Virology, University of Zurich, Zurich, Switzerland (H.F.G.); Division of Infectious Diseases, Cantonal Hospital, St. Gallen, Switzerland (P.V.); Laboratory of Virology, University Hospital of Geneva, Geneva, Switzerland (S.Y.); and The J. Craig Venter Institute, La Jolla, California (A.T.) LaurentArthur.Decosterd@chuv.ch.
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Decosterd
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D048588:Benzoxazines / Q000009:adverse effects* / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D020719:Glucuronides / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D055432:Metabolomics / Q000379:methods*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000652:urine; D018570:Risk Assessment; D013431:Sulfates / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D053719:Tandem Mass Spectrometry
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D020719:Glucuronides; D018894:Reverse Transcriptase Inhibitors; D013431:Sulfates; C585710:CYP2A6 protein, human; C585599:CYP2B6 protein, human; C104464:CYP3A protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C098320:efavirenz