Pharmacokinetics of Ceftriaxone Encapsulated in Carrier Erythrocytes in Experimental Study

Background/Objectives: Ceftriaxone (Ctx) is a third-generation cephalosporin widely used to treat infections caused by Gram-positive and Gram-negative bacteria. However, its clinical efficacy may be limited by rapid systemic elimination and suboptimal tissue distribution. Erythrocyte-based targeted drug delivery systems (TDDSs) have emerged as a promising approach to prolong drug circulation and enhance site-specific accumulation. This study investigated the pharmacokinetic profile and tissue distribution of ceftriaxone encapsulated in autologous erythrocytes (RBC-Ctx) compared with free ceftriaxone (Free-Ctx) following intravenous administration in rats. Methods: Ceftriaxone was encapsulated into autologous rat erythrocytes using a hypoosmotic hemolysis loading technique. Drug-loaded erythrocytes are called pharmacocytes. Adult male Wistar rats received a single intravenous injection of Free-Ctx or RBC-Ctx at an equivalent ceftriaxone dose of 340 mg/kg. Plasma samples were collected over 24 h for pharmacokinetic analysis, while the liver, spleen, lungs, kidneys, heart, pancreas, and skeletal muscle were harvested at 1 and 12 h for tissue distribution studies. Ceftriaxone concentrations were quantified by high-performance liquid chromatography with UV detection. Results: Erythrocyte encapsulation significantly modified the pharmacokinetic behavior of ceftriaxone. Compared with Free-Ctx, RBC-Ctx prolonged the elimination half-life (4.4 ± 0.6 vs. 1.8 ± 0.1 h), increased systemic exposure (AUC0–last, 1.6 ± 0.1 vs. 1.2 ± 0.2 mg·h/mL), reduced total body clearance (218.2 ± 11.0 vs. 294.0 ± 48.8 mL/h/kg), and increased the apparent volume of distribution at steady state (688.3 ± 61.0 vs. 435.0 ± 23.1 mL/kg). In addition, RBC-Ctx was associated with a distinct relative tissue-distribution pattern of ceftriaxone, particularly in reticuloendothelial system-rich organs such as the liver and spleen, while ceftriaxone remained detectable in several tissues at 12 h after administration. In contrast, ceftriaxone concentrations following Free-Ctx declined markedly or became undetectable over the same period. Conclusions: Encapsulation of ceftriaxone into autologous erythrocytes substantially prolonged systemic circulation, enhanced drug exposure, reduced clearance, and altered the relative tissue distribution of ceftriaxone. These findings demonstrate that erythrocyte-based carriers effectively modulate ceftriaxone pharmacokinetics and tissue distribution, supporting their potential as a targeted antibiotic delivery platform for improving antimicrobial therapy, particularly for infections involving reticuloendothelial system-associated tissues. Further studies in experimental models of infection and inflammation are warranted to evaluate therapeutic efficacy under pathological conditions and to optimize this delivery strategy.