Correlation of trimethoprim and brodimoprim physicochemical and lipid membrane interaction properties with their accumulation in human neutrophils

Abstract

Dipalmitoylphosphatidylcholine vesicles were used as a biological membrane model to investigate the interaction and the permeation properties of trimethoprim and brodimoprim as a function of drug protonation. The drug-membrane interaction was studied by differential scanning calorimetry. Both drugs interacted with the hydrophilic phospholipid head groups when in a protonated form. An experiment on the permeation of the two drugs through dipalmitoylphosphatidylcholine biomembranes showed higher diffusion rate constants when the two drugs were in the uncharged form; lowering of the pH (formation of protonated species) caused a reduction of permeation. Drug uptake by human neutrophil cells was also investigated. Both drugs may accumulate within neutrophils; however, brodimoprim does so to a greater extent. This accumulation is probably due to a pH gradient driving force, which allows the two drugs to move easily from the extracellular medium (pH approximately 7.3) into the internal cell compartments (acid pH). Once protonated, both drugs are less able to permeate and can be trapped by the neutrophils. This investigation showed the importance of the physicochemical properties of brodimoprim and trimethoprim in determining drug accumulation and membrane permeation pathways.

Enzymatic synthesis of poly(catechin)-antibiotic conjugates: an antimicrobial approach for indwelling catheters

“…Indeed, SMZ inhibits dihydropteroate synthetase (DHPS) responsible for the production of dihydrofolate from p-aminobenzoic acid. Subsequently, TMP inhibits dihydrofolate reductase (DHFR) which catalyses the formation of tetrahydrofolate from dihydrofolate (Eliopoulos and Huovinen 2001;Fresta et al 1996;Vickers et al 2009). The main advantage to produce conjugates containing antibiotic coupled to poly(catechin) lies on the ability of catechins and its polymerized derivatives, to act on and disturb the bacterial membranes.…”

“…The main advantage to produce conjugates containing antibiotic coupled to poly(catechin) lies on the ability of catechins and its polymerized derivatives, to act on and disturb the bacterial membranes. This property would potentiate the antibiotic diffusion into cell interior causing a strong bacterial reduction on the catheter surface (Fresta et al 1996). Aiming future medical applications, the viability of mammalian cells exposed to leachables of the developed antimicrobial coatings was evaluated.…”

Antimicrobial agents

“…The authors studied the effect of the drugs on membranes made from DPPC liposomes, which mimic eukaryotic cells, at different pH. 5 At lower pH values, as shown by the DSC analysis, both trimethoprim and brodimoprim are protonated, evident perturbation of the DPPC transition was observed, and no changes were seen for pure DPPC vesicles at different pH. The lipophilicity infl uences the drug's ability to diffuse through the lipid bilayer region of biological membranes.…”

“…DPPC was used to obtain a liposome for the biomembrane model (MLVs or LUVs) or to evaluate the potential of liposome as a drug delivery system. They investigated different molecules such as trimethoprim and brodimoprim (synthetic antibacterial agents), 5 leucinostatin A (an oligopeptide isolated from cultures of Paecilomyces marquandii , discussed in Section 10.4), 6 and ofl oxacin 7 using biomembrane models and a calorimetric technique. Several molecules have dissociated and undissociated forms and it is important to evaluate the equilibrium between the two forms during interaction studies.…”

Adsorptive stripping voltammetry of trimethoprim: Mechanistic studies and application to the fast determination in pharmaceutical suspensions

“…sulfamethoxazole (SMX), for the treatment of a number of bacterial infections [1][2][3][4]. Binary mixtures of TMP and SMX are current in commercial pharmaceutical preparations, like Bactrim (ratio 1:5), but TMP can be also supplied as a single agent.…”