Dolutegravir quantification in wistar rat tissues following chronic administration

Dolutegravir (DTG) has been introduced into first line combination antiretroviral therapy (ART) for HIV/AIDS. Penetration of ART into HIV reservoirs is essential to prevent continuous replication of HIV. However, accumulation of DTG in HIV reservoirs could be contributing to the adverse effects reported. We have developed and applied liquid chromatography tandem mass spectrometry (LC-MS/MS) methods to quantify DTG in wistar rat biological matrices following chronic DTG administration. DTG was detected using a Shimadzu 8040 triple quadrupole-mass spectrometer. The methods developed were in the concentration ranges of 17.5-8000 ng/mL for plasma and 15.5-16 680 ng/g for tissue matrices. Mean plasma DTG concentrations in the current study closely corresponded to plasma DTG levels reported in humans after chronic treatment. Plasma and tissue DTG concentrations were generally higher in females compared to male wistar rats, but these differences were nullified after correcting for body and organ size. Plasma DTG levels correlated with tissue DTG concentrations in the liver and gastrocnemius muscle tissue. Data suggest that body size - rather than sex - may be a major risk factor determining adverse outcomes of patients on the current DTG dosing strategy which does not account for differences in body mass. Furthermore, plasma DTG was not correlated with adipose tissue DTG concentration. This suggests that adipose may be a primary site for longer term inflammatory dysregulation and adverse outcome following DTG treatment.