title: Effects of nelfinavir and its M8 metabolite on lymphocyte P-glycoprotein activity during antiretroviral therapy.
abstract: The efflux pump P-glycoprotein decreases drug penetration into cells and tissues. To determine whether nelfinavir or its metabolites inhibit P-glycoprotein in lymphocytes from a healthy volunteer, whole blood cells from human immunodeficiency virus-negative donors were incubated either in human plasma to which nelfinavir or its M8 metabolite were added ex vivo or in plasma from human immunodeficiency virus-positive patients receiving nelfinavir. The 50% P-glycoprotein inhibitory concentrations of purified nelfinavir and M8 were 10.9 micromol/L and 29.5 micromol/L, respectively, for CD4(+) T cells and 19.3 micromol/L and >48 micromol/L, respectively, for CD8(+) T cells. Significant inhibitory activity was present in plasma from 27 of 46 patients (59%) receiving nelfinavir. Plasma nelfinavir concentrations correlated with percent inhibition on CD4(+) (rho = 0.85, P <.0001) and CD8(+) (rho = 0.83, P <.0001) T cells. The M8 concentrations correlated weakly with both inhibition and nelfinavir concentrations. On the basis of our findings in lymphocytes from a healthy volunteer exposed to plasma from human immunodeficiency virus-positive patients, we believe it is likely that CD4(+) and CD8(+) lymphocytes in patients receiving nelfinavir as therapy for human immunodeficiency virus may have P-glycoprotein inhibited by plasma concentrations of nelfinavir.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville Veterans Affairs Medical Center, TN 37203, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Donahue
authors.forename: David
authors.initials: D
authors.lastname: Dowdy
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Ratnam
authors.forename: Todd
authors.initials: T
authors.lastname: Hulgan
authors.forename: James
authors.initials: J
authors.lastname: Price
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.forename: Janet
authors.initials: J
authors.lastname: Nicotera
authors.forename: Steven
authors.initials: S
authors.lastname: Raffanti
authors.forename: Mark
authors.initials: M
authors.lastname: Becker
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D005260:Female; D017320:HIV Protease Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006679:HIV Seropositivity / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D019888:Nelfinavir / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D019888:Nelfinavir