Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans

Antimicrob Agents Chemother. 2013 Aug;57(8):3536-46. doi: 10.1128/AAC.00292-13. Epub 2013 May 13.

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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Tolerance
  • Feces / chemistry
  • Glucuronides / blood
  • Glucuronides / urine*
  • Glucuronosyltransferase / metabolism
  • HIV Integrase Inhibitors / administration & dosage
  • HIV Integrase Inhibitors / metabolism
  • HIV Integrase Inhibitors / pharmacokinetics*
  • Halogenation
  • Heterocyclic Compounds, 3-Ring / administration & dosage
  • Heterocyclic Compounds, 3-Ring / metabolism
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics*
  • Humans
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Oxazines
  • Oxidation-Reduction
  • Piperazines
  • Pyridones

Substances

  • Glucuronides
  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Oxazines
  • Piperazines
  • Pyridones
  • dolutegravir
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • UGT1A1 enzyme
  • Glucuronosyltransferase