Dolutegravir quantification in wistar rat tissues following chronic administration

Area of Science:

• Pharmacology
• HIV/AIDS Therapeutics
• Analytical Chemistry

Background:

• Dolutegravir (DTG) is a first-line antiretroviral therapy (ART) for HIV/AIDS.
• Understanding DTG distribution in biological tissues is crucial for assessing potential adverse effects and optimizing treatment.
• ART penetration into HIV reservoirs is vital for viral suppression.

Purpose of the Study:

• To develop and validate sensitive LC-MS/MS methods for quantifying DTG in wistar rat plasma and tissues.
• To investigate the pharmacokinetic profile of DTG following chronic administration in rats.
• To explore the relationship between DTG concentrations in plasma, various tissues, and potential influencing factors like sex and body size.

Main Methods:

• Development and application of liquid chromatography-tandem mass spectrometry (LC-MS/MS) for DTG quantification.
• Analysis of DTG concentrations in plasma, liver, gastrocnemius muscle, and adipose tissue of wistar rats.
• Comparison of DTG levels between male and female rats, with adjustments for body and organ size.

Main Results:

• Validated LC-MS/MS methods covered concentration ranges relevant to chronic dosing.
• Mean plasma DTG concentrations in rats mimicked human levels.
• DTG concentrations were generally higher in female rats but normalized when corrected for body size.
• Plasma DTG correlated with liver and muscle concentrations but not adipose tissue.
• Adipose tissue DTG levels suggest a potential role in long-term inflammatory issues.

Conclusions:

• Body size, rather than sex, is a significant factor influencing DTG tissue distribution and potential adverse effects.
• Current DTG dosing strategies may need adjustment to account for body mass variations.
• Adipose tissue accumulation of DTG warrants further investigation regarding its contribution to inflammatory dysregulation and adverse outcomes.