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Effect of free fatty acids on protein binding of antimicrobial agents
Abstract:
The effect of free fatty acids (FFAs) on the binding of antibiotics to human serum proteins was studied by addition of palmitic acid to albumin solutions and normal pooled serum. FFA reduced the binding of dicloxacillin, cefamandole, and sulfamethoxazole at molar ratios of FFA to albumin of greater than 2.0. In contrast, FFA enhanced the binding of benzylpenicillin, cephalothin, and cefoxitin at physiologic molar ratios of FFA to albumin. Elevated levels of FFAs induced in vivo by heparin produced similar results with dicloxacillin and benzylpenicillin. Addition of FFA to serum, but not to albumin, reduced the binding of clindamycin and trimethoprim. That the binding of these drugs was much lower in albumin than in serum suggested the presence in serum of another antibiotic-binding protein and that FFAs can modulate binding to this protein. Binding of chloramphenicol was unaffected by FFAs. The possible clinical significance of the changes in protein binding due to FFAs is discussed.
Insights
Free fatty acids (FFAs) significantly alter how antibiotics bind to human serum proteins. Depending on the antibiotic and FFA levels, binding can be reduced or enhanced, impacting drug efficacy.
Area of Science:
- Pharmacology
- Biochemistry
- Clinical Chemistry
Background:
- Antibiotic binding to serum proteins influences drug distribution and efficacy.
- Free fatty acids (FFAs) are present in human serum and their levels can fluctuate.
- Understanding FFA effects on protein binding is crucial for optimizing antibiotic therapy.
Purpose of the Study:
- To investigate the impact of free fatty acids (FFAs) on the protein binding of various antibiotics in human serum.
- To determine if FFAs differentially affect antibiotic binding to albumin versus other serum proteins.
Main Methods:
- Addition of palmitic acid (a common FFA) to albumin solutions and pooled human serum.
- In vivo study using heparin to elevate FFAs in subjects.
- Measurement of antibiotic binding to serum proteins under varying FFA conditions.
Main Results:
- FFAs reduced binding of dicloxacillin, cefamandole, and sulfamethoxazole at high molar ratios.
- FFAs enhanced binding of benzylpenicillin, cephalothin, and cefoxitin at physiological ratios.
- FFA effects on clindamycin and trimethoprim binding suggested involvement of non-albumin serum proteins.
Conclusions:
- Free fatty acids modulate antibiotic binding to human serum proteins in a drug- and concentration-dependent manner.
- The presence of other antibiotic-binding proteins in serum, besides albumin, is indicated.
- Clinical implications of FFA-mediated changes in antibiotic protein binding warrant further investigation.