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Journal of Molecular Histology

, Volume 50, Issue 6, pp 593–599 | Cite as

Investigating time dependent brain distribution of nevirapine via mass spectrometric imaging

  • Sipho Mdanda
  • Sphamandla Ntshangase
  • Sanil D. Singh
  • Tricia Naicker
  • Hendrik G. Kruger
  • Sooraj BaijnathEmail author
  • Thavendran GovenderEmail author
Original Paper

Abstract

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.

Keywords

HIV NeuroAIDS CNS BBB Pharmacokinetics and mass spectrometric imaging 

Notes

Acknowledgements

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.

Funding

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.

Ethical Approval

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).

Supplementary material

10735_2019_9852_MOESM1_ESM.doc (320 kb)
Supplementary file1 (DOC 319 kb)

References

  1. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P et al (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69:1789CrossRefGoogle Scholar
  2. Baijnath S, Moodley C, Ngcobo B, Singh SD, Kruger HG, Arvidsson PI, Naicker T, Pym A et al (2018) Clofazimine protects against Mycobacterium tuberculosis dissemination in the central nervous system following aerosol challenge in a murine model. Int J Antimicrob Agents 51:77–81CrossRefGoogle Scholar
  3. 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
  4. Calmy A, Pascual F, Ford N (2004) First-line and second-line antiretroviral therapy. Lancet 364:329.  https://doi.org/10.1016/S0140-6736(04)16716-0 CrossRefPubMedGoogle Scholar
  5. Carr A, Cooper DA (1996) Current Clinical Experience with Nevirapine for HIV Infection. Antivir Chemother 4:299–304CrossRefGoogle Scholar
  6. Chiang M-C, Dutton RA, Hayashi KM, Lopez OL, Aizenstein HJ, Toga AW, Becker JT, Thompson PM (2007) 3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry. NeuroImage 34:44–60.  https://doi.org/10.1016/j.neuroimage.2006.08.030 CrossRefPubMedGoogle Scholar
  7. Churchill M, Nath A (2013) Where does HIV hide? a focus on the central nervous system. Curr Opin HIV AIDS 8:165–169.  https://doi.org/10.1097/COH.0b013e32835fc601 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Clark DE (2003) In silico prediction of blood–brain barrier permeation. Drug Discov Today 8:927–933.  https://doi.org/10.1016/S1359-6446(03)02827-7 CrossRefPubMedGoogle Scholar
  9. Clifford DB, Ances BM (2013) HIV-associated neurocognitive disorder. Lancet Infect Dis 13:976–986.  https://doi.org/10.1016/S1473-3099(13)70269-X CrossRefPubMedPubMedCentralGoogle Scholar
  10. Clifford DB, Evans S, Yang Y, Acosta EP, Ribaudo H, Gulick RM, As Study T (5097s) Long-term impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals (ACTG 5097s). HIV Clin Trials 10:343–355.  https://doi.org/10.1310/hct1006-343 CrossRefGoogle Scholar
  11. Committee for Canadian Paediatric ARG (2001) Nevirapine use to reduce mother-to-child transmission of HIV in Canada. Paediatr Child Health 6:121–122CrossRefGoogle Scholar
  12. Cooper C, Van Heeswijk R (2007) Once-daily nevirapine dosing: a pharmacokinetics, efficacy and safety review. HIV Med 8:1–7CrossRefGoogle Scholar
  13. De Clercq E (2009) Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J Antimicrob Agents 33:307–320.  https://doi.org/10.1016/j.ijantimicag.2008.10.010 CrossRefPubMedGoogle Scholar
  14. De Oliveira F, do Olival G, de Oliveira A, (2015) Central nervous system antiretroviral high penetration therapy. J AIDS Clin Res 6:529CrossRefGoogle Scholar
  15. Demeule M, Regina A, Jodoin J, Laplante A, Dagenais C, Berthelet F, Moghrabi A, Beliveau R (2002) Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood-brain barrier. Vasc Pharmacol 38:339–348CrossRefGoogle Scholar
  16. Ene L, Duiculescu D, Ruta SM (2011) How much do antiretroviral drugs penetrate into the central nervous system? J Med Life 4:432–439PubMedPubMedCentralGoogle Scholar
  17. Engelhardt B, Sorokin L (2009) The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31:497–511.  https://doi.org/10.1007/s00281-009-0177-0 CrossRefPubMedGoogle Scholar
  18. Erickson DA, Mather G, Trager WF, Levy RH, Keirns JJ (1999) Characterization of the in vitro biotransformation of the HIV-1 reverse transcriptase inhibitor nevirapine by human hepatic cytochromes P-450. Drug Metab Dispos 27:1488PubMedGoogle Scholar
  19. 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
  20. Hellmuth J, Valcour V, Spudich S (2015) CNS reservoirs for HIV: implications for eradication. J Virus Erad 1:67–71PubMedPubMedCentralGoogle Scholar
  21. 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
  22. Lamson MJ, Sabo JP, MacGregor TR, Pav JW, Rowland L, Hawi A, Cappola M, Robinson P (1999) Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers. Biopharm Drug Dispos 20:285–291CrossRefGoogle Scholar
  23. Laughton B, Cornell M, Boivin M, Van Rie A (2013) Neurodevelopment in perinatally HIV-infected children: a concern for adolescence. JIAS 16:18603.  https://doi.org/10.7448/ias.16.1.18603 CrossRefGoogle Scholar
  24. 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
  25. 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
  26. Lipinski CA (2004) Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today 1:337–341.  https://doi.org/10.1016/j.ddtec.2004.11.007 CrossRefGoogle Scholar
  27. Mdanda S, Baijnath S, Shobo A, Singh SD, Maguire GE, Kruger HG, Arvidsson PI, Naicker T et al (2017) Lansoprazole-sulphide, pharmacokinetics of this promising anti-tuberculous agent. Biomed Chromatogr 31:12CrossRefGoogle Scholar
  28. Ntshangase S, Shobo A, Kruger HG, Asperger A, Niemeyer D, Arvidsson PI, Govender T, Baijnath S (2017) The downfall of TBA-354–a possible explanation for its neurotoxicity via mass spectrometric imaging. Xenobiotica 48:938–944CrossRefGoogle Scholar
  29. Pal D, Kwatra D, Minocha M, Paturi DK, Budda B, Mitra AK (2011) Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals. Life Sci 88:959–971.  https://doi.org/10.1016/j.lfs.2010.09.012 CrossRefPubMedGoogle Scholar
  30. Pamreddy A, Baijnath S, Naicker T, Ntshangase S, Mdanda S, Lubanyana H, Kruger HG, Govender T (2018) Bedaquiline has potential for targeting tuberculosis reservoirs in the central nervous system. RSC Adv 8:11902–11907CrossRefGoogle Scholar
  31. Price RW, Spudich S (2008) Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 197:294–306CrossRefGoogle Scholar
  32. 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
  33. 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
  34. Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A et al (2016) HIV-associated neurocognitive disorder–pathogenesis and prospects for treatment. Nat Rev Neurol 12:234–248.  https://doi.org/10.1038/nrneurol.2016.27 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Slogrove AL, Sohn AH (2018) The global epidemiology of adolescents living with HIV: time for more granular data to improve adolescent health outcomes. Curr Opin HIV AIDS 13:170–178.  https://doi.org/10.1097/COH.0000000000000449 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Tau GZ, Peterson BS (2010) Normal development of brain circuits. Neuropsychopharmacology 35:147CrossRefGoogle Scholar
  37. Teklezgi BG, Pamreddy A, Baijnath S, Gopal ND, Naicker T, Kruger HG, Govender T (2017) Post heroin dose tissue distribution of 6-monoacetylmorphine (6-MAM) with MALDI imaging. J Mol Histol 48:285–292CrossRefGoogle Scholar
  38. Teklezgi BG, Pamreddy A, Baijnath S, Kruger HG, Naicker T, Gopal ND, Govender T (2018) Time-dependent regional brain distribution of methadone and naltrexone in the treatment of opioid addiction. Addict Biol.  https://doi.org/10.1111/adb.12609 CrossRefPubMedGoogle Scholar
  39. Varatharajan L, Thomas SA (2009) The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antivir Res 82:99–109.  https://doi.org/10.1016/j.antiviral.2008.12.013 CrossRefGoogle Scholar
  40. Wynn HE, Brundage RC, Fletcher CV (2002) Clinical implications of CNS penetration of antiretroviral drugs. CNS Drugs 16:595–609CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Catalysis and Peptide Research UnitUniversity of KwaZulu-NatalDurbanSouth Africa
  2. 2.AnSynth PTY LTDDurbanSouth Africa
  3. 3.Biomedical Resource UnitUniversity of KwaZulu-NatalDurbanSouth Africa

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