Antibacterial Activity of β-Cyclodextrin and 2-Hydroxypropyl-β-Cyclodextrin Trimethoprim Complexes
- 1 ,
Copyright: © 2021 Hsien-Kuo Sun, Madhumathi Seshadri, Scott Lingard, Wayne Monaghan, Joan Faoagali, Enoch Chan, Helen McDonald, Todd Houston, Michelle King, Ian Peak, Jennifer C. Wilson, Alison Haywood, Briohny Spencer, Perrea Dunn and Gary Dean Grant. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Problem statement: Cyclodextrin complexation has previously been shown to improve the solubility and dissolution properties of trimethoprim; however, no report provides an account of the effect cyclodextrin complexation has on the antibacterial activity of this agent. Approach: β-cyclodextrin and 2-hydroxypropyl β-cyclodextrin inclusion complexes of trimethoprim were prepared and confirmed by differential scanning calorimetry and proton nuclear magnetic resonance. The in-vitro antibacterial activity, in terms of minimum inhibitory concentrations, of cyclodextrin-drug complexes were compared to uncomplexed free trimethoprim by a broth-microdilution method against several sensitive and resistant Gram-positive and Gram-negative bacteria. The effect of complexation on the apparent permeability coefficients was also determined using a Caco-2 permeability assay to account for potential alterations in bioavailability that could influence in-vivo antibacterial activity. Results: Inclusion complexation of trimethoprim with both unsubstituted and hydroxylated versions of β-cyclodextrin produced a reduction in the MIC80 required to inhibit the growth of S. aureus ATCC 29213, S. pneumoniae ATCC 4961, S. epidermidis ATCC 14990 and E. coli ATCC 25922 (p>0.05). The effect was limited to bacteria normally susceptible to trimethoprim. Neither complex negatively affected the antibacterial activity of trimethoprim. Hydroxypropyl-β-cyclodextrin and β-cyclodextrin inclusion complexes significantly (p<0.01) increased the apparent intestinal permeability of trimethoprim by 39.8 and 56.1%, respectively. Considering the effect cyclodextrin inclusion complexation has on the antibacterial activity of trimethoprim, the improved intestinal permeability of these complexes has the potential to improve the in-vivo antibacterial activity of the agent by enhancing the steady-state concentration of the drug when dosed orally. Conclusion: These results would suggest that physical complexation with either of these cyclodextrins would provide a feasible strategy to improve the pharmaceutical and pharmacokinetic properties of trimethoprim.
- 3,000 Views
- 3,416 Downloads
- 5 Citations
- Antibacterial activity
- inclusion complex
- antimicrobial activity
- caco-2 cells
- Differential Scanning Calorimetry (DSC)
- Minimum Inhibitory Concentrations (MIC)
- S. aureus