A Novel Cryptococcal Meningitis Therapy: The Combination of Amphotericin B and Posaconazole Promotes the Distribution of Amphotericin B in the Brain Tissue.

Abstract

The deficient brain tissue distribution of amphotericin B (AMPB) seriously restricts its treatment for the clinical efficacy of cryptococcus neoformans meningitis (CNM). We strive to develop a tactic to increase its concentration in brain tissue. We aimed to investigate whether the combination of AMPB and posaconazole (POS) could be more effective in the treatment of CNM and to elucidate its potential mechanisms. HPLC analysis was used to analyze the concentration of AMPB in mouse serum, brain tissue, and BCECs cells. Schrodinger molecular docking, in vitro plasma balance dialysis, and ultrafiltration analysis were performed to evaluate the combinative effect of AMPB and POS with serum albumin and POS on AMPB plasma protein binding. H&E staining and colonization culture experiment of CN were employed to assess the effect of POS on the efficacy of AMPB. POS + AMPB significantly reduced the concentration of plasma total AMPB and increased its concentration in the brain tissue. However, the P-gp inhibitor zosuquidar, BCRP inhibitor Ko143, and a common inhibitor of both, elacridar, had no significant effect on its concentration. Molecular docking, balance dialysis, and ultrafiltration analysis showed that AMPB and POS had potential binding properties to serum albumin. Meanwhile, 4 and 8 μg/mL POS could significantly increase the concentration of free AMPB in plasma. POS and three inhibitors all had no significant effect on the uptake of AMPB by BCECs, but serum albumin had. The therapeutic effect of CNM in mice was confirmed that AMPB and AMPB+POS could restrain the infiltration of neutrophils and lymphocytes in cortical neurons and improve the bleeding and markedly inhibit the proliferation of CN. Collectively, we propose that POS competitively binds to the plasma protein sites of AMPB, thereby increasing its level in the brain tissue. Meanwhile, POS could enhance the efficacy of AMPB in the treatment of CNM, which may be independent of P-gp and BCRP proteins.

• Authors: Ming Yang, Lin Cheng, Qing Dai, Bo Yang, Qian Yuan, MingJie Yu, Wei Feng, Fengjun Sun, Peiyuan Xia
• Journal: BioMed research international (Biomed Res Int) Vol. 2020 Pg. 8878158 ( 2020) ISSN: 2314-6141 [Electronic] United States
• PMID: 33313322 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Ming Yang et al.

Chemical References

• 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Abcg2 protein, mouse
• Dibenzocycloheptenes
• Diketopiperazines
• Heterocyclic Compounds, 4 or More Rings
• Quinolines
• Serum Albumin
• Triazoles
• posaconazole
• Amphotericin B
• zosuquidar trihydrochloride

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (metabolism)
• Amphotericin B (administration & dosage, pharmacokinetics)
• Animals
• Blood-Brain Barrier (metabolism)
• Brain (drug effects)
• Cryptococcus neoformans
• Dibenzocycloheptenes (administration & dosage)
• Diketopiperazines (administration & dosage)
• Disease Models, Animal
• Heterocyclic Compounds, 4 or More Rings (administration & dosage)
• Humans
• Male
• Meningitis, Cryptococcal (drug therapy)
• Mice
• Molecular Docking Simulation
• Quinolines (administration & dosage)
• Serum Albumin (metabolism)
• Tissue Distribution
• Triazoles (administration & dosage)