Clinical Role of Protein Binding of Quinolones

Abstract

Protein binding of antibacterials in plasma and tissues has long been considered a component of their pharmacokinetic parameters, playing a potential role in distribution, excretion and therapeutic effectiveness. Since the beginning of the 'antibacterial era', this factor has been extensively analysed for all antibacterial classes, showing that wide variations of the degree of protein binding occur even in the same antibacterial class, as with beta-lactams. As the understanding of protein binding grew, the complexity of the binding system was increasingly perceived and its dynamic character described. Studies of protein binding of the fluoroquinolones have shown that the great majority of these drugs exhibit low protein binding, ranging from approximately 20 to 40% in plasma, and that they are bound predominantly to albumin. The potential role in pharmacokinetics-pharmacodynamics of binding of fluoroquinolones to plasma, tissue and intracellular proteins has been analysed, but it has not been established that protein binding has any significant direct or indirect impact on therapeutic effectiveness. Regarding the factors influencing the tissue distribution of antibacterials, physicochemical characteristics and the small molecular size of fluoroquinolones permit a rapid penetration into extravascular sites and intracellularly, with a rapid equilibrium being established between intravascular and extravascular compartments. The high concentrations of these drugs achieved in tissues, body fluids and intracellularly, in addition to their wide antibacterial spectrum, mean that fluoroquinolones have therapeutic effectiveness in a large variety of infections. The tolerability of quinolones has generally been reported as good, based upon long experience in using pefloxacin, ciprofloxacin and ofloxacin in clinical practice. Among more recently developed molecules, good tolerability has been reported for levofloxacin, moxifloxacin and gatifloxacin, but certain other new compounds have been removed from the market because of renal, hepatic and cardiac toxicity. To what extent the protein binding of fluoroquinolones can play a role in their tolerability is unclear. In terms of drug-drug interactions, the role of protein binding is questionable: several drug combinations can be responsible for toxicity, such as with beta-lactams, metronidazole, theophylline, nonsteroidal anti-inflammatory agents or a series of drugs used for cardiac diseases, but protein binding does not seem to be involved in these interactions. In conclusion, protein binding of fluoroquinolones appears to be a complex phenomenon, but has no clear role in therapeutic effectiveness or toxicity.

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

“…Most fluoroquinolones are moderately lipophilic drugs with a molecular mass of around 300 Da and low binding to plasma proteins (approximately 20 to 40%) (21). Around the physiological pH, most agents are uncharged, which favors their CNS penetration.…”

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Impact of Preparative and Incubation Methods on Different Pharmacodynamic Endpoints of ß-Lactams, Macrolides, or Fluoroquinolones Against Gram-positive and Gram-negative Bacteria-Part I

“…For example, protein binding of clarithromycin may be as low as of 42 to 50% over a concentration range of 0.25 to 0.5 mg/L [54], or as high as 72% over a concentration range of 0.04 to 1.0 mg/L [55,56]. Protein binding of moxifloxacin being concentration independent was found to range from 25% [57] to 52% [58]. Such differences really matter, as the free fraction used as basis for PK/PD calculations could be assumed to be as low as 30% and 48% or as high as 60% and 75%, respectively.…”

Protein Binding of Antimicrobials: Methods for Quantification and for Investigation of its Impact on Bacterial Killing

“…The relevance of PB on PKs and the microbiological efficacy of an antibiotic were considered clinically important in case of highly bound agents (17). It is well-established that only the protein unbound fraction of a drug in plasma can readily penetrate into and equilibrate with the extravascular space (3). Sufficient tissue penetration of drugs is, in turn, a prerequisite for successful treatment of the majority of bacterial infections, which occur in the interstitial fluid (ISF) rather than in the blood (18).…”

“…In contrast, no general consensus has been reached, whether PB also pharmacodynamically impacts antimicrobial activity by reducing the free, i.e., nonprotein-bound, fraction of an antibiotic (3,4). The unfavorable effect of PB on bacterial killing is generally accepted for β-lactams (5,6), whereas doubts about the usefulness of extrapolation of findings from β-lactams to other antimicrobial classes, such as fluoroquinolones, persist (3,4). There is currently no standardization of in vitro pharmacodynamic (PD) models, which account for the impact of PB of antimicrobials (7).…”

“…The implications of PB on the antimicrobial efficacy of an antibiotic shall be outlined and the current position of PB in in vitro PD models of antibiotics will be discussed. As extensive reviews on impact of PB on PK of drugs are available, the present work will not go into details on this topic (3,(10)(11)(12)(13)(14).…”