Mass spectrometric investigations into the brain delivery of abacavir, stavudine and didanosine in a rodent model

Abstract

1. HIV replication in the brain is unopposed due to reduced antiretroviral drug penetration into the central nervous system (CNS). Prevalence of HIV-associated neurocognitive disorder (HAND) has increased severely in patients living with HIV despite current treatments. The aims of this study were to evaluate the brain bio-distribution of alternative nucleoside reverse transcriptase inhibitors, abacavir, stavudine and didanosine in the CNS and to determine their localization patterns in the brain.

2. Sprague-Dawley rats received 50 mg kg⁻¹ single i.p dose of each drug. Mass spectrometric techniques were then used to investigate the pharmacokinetics and localization patterns of these drugs in the brain using LC-MS/MS and mass spectrometric imaging (MSI), respectively.

3. Abacavir, stavudine and didanosine reached the Brain C_max with concentration of 831.2, 1300 and 43.37 ngmL⁻¹, respectively. Based on MSI analysis Abacavir and Stavudine were located in brain regions that are strongly implicated in the progression of HAND.

4. Abacavir and Stavudine penetrated into CNS, reaching a C_max that was above the IC₅₀ for HIV (457.6 and 112.0 ngmL⁻¹, respectively), however, it was noted ddI showed poor entry within the brain, therefore, it is recommended that this drug cannot be considered for treating CNS-HIV.

Keywords:

• HIV neurocognitive disorder
• nucleoside reverse transcriptase inhibitors
• mass spectrometric techniques and central nervous system

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors wish to thank National Research Foundation (NRF, SA), Aspen Pharmacare, MRC and the University of KwaZulu-Natal (Durban, SA), for financial support.