The comparative disposition and metabolism of dolutegravir, a potent HIV-1 integrase inhibitor, in mice, rats, and monkeys

Abstract

1. Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12 mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28 L/kg, respectively) with terminal elimination half-life approximately 6 h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension.

2. Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species.

3. Following oral administration to rats, [¹⁴C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24 h.

4. The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.

• Distribution
• HIV-1 integrase inhibitor
• metabolite identification
• pharmacokinetics
• radiochemical profiling

Acknowledgements

We thank Todd Baughman for support during discovery phase (glutathione trapping), John Ulrich, and Vishal Shah for their technical support and Michael O’Mara and Gary Boyle for assisting in the preparation and review of this manuscript.

Declaration of interest

The authors report no conflicts of interest. The authors are employees of GSK and Shionogi and alone are responsible for the content and writing of the paper. This work was supported by ViiV Healthcare.