title: Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans.
abstract: The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [(14)C]dolutegravir at a dose of 20 mg (80 μCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half-lives (t1/2) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Castellino
authors.forename: Lee
authors.initials: L
authors.lastname: Moss
authors.forename: David
authors.initials: D
authors.lastname: Wagner
authors.forename: Julie
authors.initials: J
authors.lastname: Borland
authors.forename: Ivy
authors.initials: I
authors.lastname: Song
authors.forename: Shuguang
authors.initials: S
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: Sherene S
authors.initials: SS
authors.lastname: Min
authors.forename: Igor
authors.initials: I
authors.lastname: Goljer
authors.forename: Amanda
authors.initials: A
authors.lastname: Culp
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
authors.forename: Paul M
authors.initials: PM
authors.lastname: Savina
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004361:Drug Tolerance; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000097:blood / Q000652:urine*; D014453:Glucuronosyltransferase / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D054879:Halogenation; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010078:Oxazines; D010084:Oxidation-Reduction; D010879:Piperazines; D011728:Pyridones; D000099148:UGT1A1 Enzyme; D000099226:Dolutegravir
chemical_list: D051544:Cytochrome P-450 CYP3A; D020719:Glucuronides; D014453:Glucuronosyltransferase; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099148:UGT1A1 Enzyme; D000099226:Dolutegravir; C510163:CYP3A4 protein, human