Protein Binding in Translational Antimicrobial Development-Focus on Interspecies Differences

Abstract

Background/Introduction: Plasma protein binding (PPB) continues to be a key aspect of antibiotic development and clinical use. PPB is essential to understand several properties of drug candidates, including antimicrobial activity, drug-drug interaction, drug clearance, volume of distribution, and therapeutic index. Focus areas of the review: In this review, we discuss the basics of PPB, including the main drug binding proteins i.e., Albumin and α-1-acid glycoprotein (AAG). Furthermore, we present the effects of PPB on the antimicrobial activity of antibiotics and the current role of PPB in in vitro pharmacodynamic (PD) models of antibiotics. Moreover, the effect of PPB on the PK/PD of antibiotics has been discussed in this review. A key aspect of this paper is a concise evaluation of PPB between animal species (dog, rat, mouse, rabbit and monkey) and humans. Our statistical analysis of the data available in the literature suggests a significant difference between antibiotic binding in humans and that of dogs or mice, with the majority of measurements from the pre-clinical species falling within five-fold of the human plasma value. Conversely, no significant difference in binding was found between humans and rats, rabbits, or monkeys. This information may be helpful for drug researchers to select the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. Furthermore, state-of-the-art methods for determining PPB such as equilibrium dialysis, ultracentrifugation, microdialysis, gel filtration, chromatographic methods and fluorescence spectroscopy are highlighted with their advantages and disadvantages.

Changes in plasma alpha‐1 acid glycoprotein following hemorrhagic trauma: Possible role in dose differences of ALM drug therapy in rat and pig resuscitation

“…Notwithstanding interspecies and strain differences, serum AGP of any one species can change rapidly in response to changing physiological status such as animal handling, housing, stress, age, health status, surgical preparation, activity level, and the presence of inflammation, infection, or injury. The specificity of the analytical AGP method may also contribute to differences where older studies used multi‐step electrophoretic immunodiffusion procedures, 8 while more recent studies use highly specific ELISA 2,3,27 . In summary, when comparing AGP values in the serum of animals and humans, and before standard reference values can be established, it is important to understand the procedural methods and health status of the animal prior to measurement.…”

“…Alpha-1 acid glycoprotein (AGP) is a significant high-affinity/lowcapacity drug binding and acute-phase protein present in animals and humans. 3,5 With respect to changes in AGP in rats and pigs after hemorrhagic shock, we report the following: (1) mean baseline plasma AGP concentration is 83-fold higher in pigs than in rats; (2) surgical procedures alone were associated with a ~10-fold increase in AGP in rats and a contrasting 21% decrease in pigs; and (3) after hemorrhage and resuscitation, AGP levels in rats decreased 26% over 5 h with little change over the next 3 days, while AGP values in pigs decreased ~8% over 60 min and less than 10% decrease over the next 6 h. We will now discuss these findings, and the possible clinical relevance to higher ALM-doses required in pigs to resuscitate following hemorrhagic shock.…”

Oral ciprofloxacin activity against ceftriaxone-resistantEscherichia coliin anin vitrobladder infection model

“…Antibiotic protein binding, which is an important consideration in plasma PK, is less of an issue when considering free-drug activity and total drug measurements in urine, given the renal excretion of unbound drug and the paucity of albumin found in urine in patients with normal renal glomerular function. 39 , 40 Urinary ciprofloxacin PK variability has been modelled in relation to urine output (1 versus 2.5 L/day), healthy young adults versus elderly, and circadian changes in diuresis and absorption. 41 Such variability in urinary PK is not unique to ciprofloxacin.…”

Developmental Pharmacokinetics of Antibiotics Used in Neonatal ICU: Focus on Preterm Infants

“…On the opposite side, an increased binding rate will result in the reduction of free, active drug concentrations, which may lead to the decreased antimicrobial activity of antibacterial agents in the site of infection, which is extravascular typically. It was also shown that the rate of plasma protein binding of antibiotics can affect the extent of their antimicrobial activity [ 129 ].…”