Enrofloxacin: Mechanism of Action and Pharmacokinetics

General Description

Enrofloxacin, a fluoroquinolone antibiotic, targets bacterial DNA enzymes, primarily DNA gyrase and topoisomerase IV, inhibiting their function and halting DNA replication. Its effects can be bactericidal or bacteriostatic, depending on concentration. The pharmacokinetics of enrofloxacin include high bioavailability and rapid absorption, influenced by factors such as species, nutritional status, and ion presence. It distributes widely in body tissues and is primarily eliminated through renal pathways, with significant variability in elimination half-life among species. Understanding these mechanisms is crucial for optimizing enrofloxacin's clinical application in treating bacterial infections effectively.

Figure 1. Enrofloxacin

Mechanism of Action

The targets of enrofloxacin, like other quinols, are enzymes that control DNA topology: gyrase and topoisomerase IV. Their activities facilitate the processes of DNA replication, recombination, and gene expression. As heterotetramers, these enzymes are composed of two GyrA and two GyrB subunits, in the case of gyrase, or their homologs ParC and ParE in topoisomerase IV. The GyrA and ParC subunits have a tyrosine residue in the active site that is involved in DNA strand breakage, while the GyrB and ParC subunits have the domains required for DNA strand re-ligation. DNA gyrase, by introducing negative supercoils, alleviates topological stresses, allowing replication complexes to move along the DNA. It works by coiling DNA into a positive supercoil and then moving the duplex region accordingly, breaking and rejoining. The speed of the process is regulated by the availability of ATP (the abundance of this nucleotide accelerates the process). Topoisomerase IV activity differs from gyrase activity. Although it can remove positive and negative supercoils, it cannot actively unwind dsDNA. In addition, it has a greater ability to resolve DNA strands.¹

Bactericidal and Bacteriostatic Effects

The disruption of enzymatic activities described above is associated with the formation of complexes between DNA and gyrase or topoisomerase IV. When conformational changes occur, quinolone prevents the rejoining of torn DNA strands, and the enzyme itself is trapped on the DNA. In the case of gyrase, rapid inhibition occurs, which is associated with activity upstream of the replication fork. A different situation—the subsequent inhibition of replication—occurs with quinolone–topoisomerase IV-DNA complexes. This is related to the activity of the enzyme downstream of the replication fork. Complex formation is reversible, which is responsible for the bacteriostatic action of the compounds. In contrast, bactericidal activity is considered to be a separate phenomenon from complex formation. The first proposal of the bactericidal effect of enrofloxacin based on free DNA end release, not just complex formation, came from a sedimentation analysis of isolated bacterial nucleoids.

Two molecules of enrofloxacin bind non-covalently to the DNA-topoisomerase complex (II or IV) near the tyrosine residue in the active site. After binding, enrofloxacin induces conformational changes in the enzyme. This results in the formation of an enrofloxacin–gyrase/topoisomerase IV-DNA complex. The natural consequence of this process is the inhibition of DNA replication. Low concentrations of the antibiotic can trigger the SOS response (a bacteriostatic effect), while concentrations of the antibiotic can fragment the bacterial chromosome, leading to cell death (a bactericidal effect).¹

Pharmacokinetics

Absorption

Enrofloxacin exhibits high bioavailability and fast absorption rates following various routes of administration, including intramuscular, subcutaneous, and oral methods. However, there are variations observed with oral administration in ruminants, indicating that species-specific differences can influence the absorption profile. Notably, the nutritional status of the animal also plays a critical role; studies have shown that enrofloxacin absorption is significantly enhanced in fasted pigs compared to those that are fed. Additionally, the presence of ions, particularly calcium and magnesium, can markedly reduce the bioavailability of enrofloxacin when administered in water high in these minerals. This effect highlights the importance of considering dietary and environmental factors when planning treatment regimens. Recent advancements in drug delivery technologies, such as using polyvinylpyrrolidone for enhanced absorption and the development of transdermal sustained release systems, are promising strategies aimed at optimizing the bioavailability of enrofloxacin. ²

Distribution

The distribution of enrofloxacin within the body is essential for its therapeutic efficacy. Once absorbed, the pharmacokinetics of enrofloxacin are influenced by its chemical properties and the individual characteristics of the patient. Enrofloxacin is known to distribute widely across various tissues, including the lungs, liver, kidneys, and other organs, where it can exert its antibacterial effects. The concentration-dependent nature of enrofloxacin also plays a significant role in its distribution profile. Importantly, protein binding can significantly affect the free concentration of enrofloxacin in the bloodstream, thereby influencing its tissue distribution and overall effectiveness. Understanding how enrofloxacin disperses in different species is vital for optimizing dosing strategies and maximizing therapeutic outcomes. ²

Elimination

The elimination of enrofloxacin varies substantially among different species, emphasizing the necessity for tailored dosing regimens. After intravenous administration, the elimination half-life of enrofloxacin can range significantly, with reported values of 1.5 hours in cows to as long as 27.9 hours in Atlantic horseshoe crabs. This variability is crucial in determining how frequently enrofloxacin should be administered to achieve therapeutic levels. The metabolic pathway of enrofloxacin typically involves biotransformation into ciprofloxacin, which is also active but eliminated by both renal and hepatic routes. In contrast, enrofloxacin primarily undergoes renal elimination. Interestingly, studies in specific species, such as green sea turtles, indicate profound differences in elimination times for enrofloxacin and its metabolite ciprofloxacin, likely due to their distinct elimination mechanisms. Furthermore, emerging evidence suggests that intestinal recirculation through bile excretion could be a significant route for enrofloxacin elimination in certain aquatic species, such as Yellow River carp, which opens new avenues for research into its pharmacokinetic behavior in diverse environments. ²

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