Investigating time dependent brain distribution of nevirapine via mass spectrometric imaging
Central nervous system (CNS) HIV infection causes brain tissue inflammation and tissue deficit that contributes to neuroAIDS. This complication is escalated by the blood–brain barrier (BBB), which prevents easy access to antiretroviral drugs entering the CNS. In this study the aims were to investigate the BBB membrane penetration and brain localization patterns of Nevirapine (NVP) using Imaging Mass Spectrometry (MSI). Sprague–Dawley rats received an intraperitoneal dose of NVP (50 mg kg−1). Plasma and brain samples were harvested, and mass spectrometric methods were then applied to determine the pharmacokinetic properties and localization patterns of NVP in the brain. The pharmacokinetic parameters demonstrated a rapid bio-distribution of NVP in plasma and brain. The plasma Cmax was 6320 ng mL−1 and the brain Cmax was 1923 ng mL−1, both at a Tmax of 0.25 h. MSI of coronal brain sections showed that NVP penetrated and localized in the brain regions implicated with the development of HIV associated neurodegeneration. NVP has great potential to combat neuroAIDS.
KeywordsHIV NeuroAIDS CNS BBB Pharmacokinetics and mass spectrometric imaging
The Authors wish to acknowledge Biomedical Research Unit located in University of KwaZulu-Natal, Dr Sanil D. Singh and Dr Linda Bester for the support during animal experiments.
The authors wish to thank National Research Foundation (NRF, SA), Aspen Pharmacare, South African Medical Research Council (SAMRC) and the University of KwaZulu-Natal (Durban, South Africa), for financial support.
Compliance with ethical standards
Conflict of interests
The authors declare that they have no competing interests.
All animal experimentation was carried out with approval from the Institutional Animal Research Ethics Committee of the University of KwaZulu–Natal (protocol reference number AREC/007/017D).
- Brouwers P, Hendricks M, Lietzau JA, Pluda JM, Mitsuya H, Broder S, Yarchoan R (1997) Effect of combination therapy with zidovudine and didanosine on neuropsychological functioning in patients with symptomatic HIV disease: a comparison of simultaneous and alternating regimens. AIDS 11:59–66CrossRefGoogle Scholar
- Gray LR, Tachedjian G, Ellett AM, Roche MJ, Cheng WJ, Guillemin GJ, Brew BJ, Turville SG et al (2013) The NRTIs lamivudine, stavudine and zidovudine have reduced HIV-1 inhibitory activity in astrocytes. PLoS ONE 8:e62196. https://doi.org/10.1371/journal.pone.0062196 CrossRefPubMedPubMedCentralGoogle Scholar
- Kore I, Ananworanich J, Valcour V, Fletcher JLK, Chalermchai T, Paul R, Reynolds J, Tipsuk S et al (2015) Neuropsychological impairment in acute HIV and the effect of immediate antiretroviral therapy. J Acquir Immune Defic Syndr 70:393–399. https://doi.org/10.1097/QAI.0000000000000746 CrossRefPubMedPubMedCentralGoogle Scholar
- Laurito TL, Santagada V, Caliendo G, Oliveira CH, Barrientos-Astigarraga RE, De Nucci G (2002) Nevirapine quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study. J Mass Spectrom 37:434–441CrossRefGoogle Scholar
- Lawler K, Jeremiah K, Mosepele M, Ratcliffe SJ, Cherry C, Seloilwe E, Steenhoff AP (2011) Neurobehavioral effects in HIV-positive individuals receiving highly active antiretroviral therapy (HAART) in Gaborone. Botswana. PLoS ONE 6(2):e17233. https://doi.org/10.1371/journal.pone.0017233 CrossRefPubMedGoogle Scholar
- Puthanakit T, Ananworanich J, Vonthanak S, Kosalaraksa P, Hansudewechakul R, van der Lugt J, Kerr SJ, Kanjanavanit S et al (2013) Cognitive function and neurodevelopmental outcomes in HIV-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the PREDICT neurodevelopmental study. Pediatr Infect Dis J 32:501–508. https://doi.org/10.1097/INF.0b013e31827fb19d CrossRefPubMedPubMedCentralGoogle Scholar
- Ruel TD, Boivin MJ, Boal HE, Bangirana P, Charlebois E, Havlir DV, Rosenthal PJ, Dorsey G et al (2012) Neurocognitive and motor deficits in HIV-Infected ugandan children with high CD4 cell counts. Clin Infect Dis 54:1001–1009. https://doi.org/10.1093/cid/cir1037 CrossRefPubMedPubMedCentralGoogle Scholar