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BACKGROUND: Levofloxacin concentrations do not always reach desired levels when administered at a standard dose; therefore, measuring levofloxacin levels in the blood plasma or other alternative matrices, such as the saliva, can help clinicians make informed decisions concerning the dosage and mode of administration. Saliva, as an object of research, is of particular interest due to the simplicity and non-invasiveness of sampling for analysis. AIM: This study aimed to determine the comparative pharmacokinetics of levofloxacin in the blood plasma and saliva of patients with community-acquired pneumonia (CAP) and assess the possibility of using saliva as an alternative sampling matrix in pharmacokinetic studies. MATERIALS AND METHODS: Levofloxacin concentration in the blood plasma and saliva of patients with CAP and volunteers was determined using high-performance liquid chromatography on an Agilent 1200 liquid chromatography (Agilent, USA) with an ultraviolet detector. Sample preparation of bioassays was performed using protein precipitation. Patients and volunteers took 1 tablet (500 mg dose) of levofloxacin per os in the morning, on an empty stomach. Blood and saliva samples were taken at the initial blood sample and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after taking the drug. The pharmacokinetic parameters were determined, namely Cmax as the peak concentration of the drug; Тmax as the time-to-peak concentration; AUC0t as the area under the pharmacokinetic curve in the range from 0 to the last experimental point on the curve; AUC0 as the total area under the pharmacokinetic curve from zero to infinity; t1/2 as half-life period; MRT as mean residence time of the drug in the blood (h); Cl/F as clearance; and Vss/F as the total distribution volume. RESULTS: The maximum blood plasma and saliva concentration of patients was reached 1 h after taking the drug and amounted to Сmax=5.982.89 g/ml and Сmax=4.413.83 g/ml, respectively. Additionally, the maximum concentrations in blood plasma and saliva were recorded 1 h after taking the drug as 5.523.07 g/ml and 3.250.85 g/ml, respectively, in healthy volunteers. The correlation coefficient (r) between the mean values of the levofloxacin concentrations in the blood plasma and the saliva of patients with CAP was 0.953 and that of healthy volunteers was 0.977. DISCUSSION: Pharmacokinetic parameters were calculated based on blood plasma and saliva concentrations. Their comparative analysis revealed almost the same absorption rate from the gastrointestinal tract in patients and healthy volunteers. Correlation-regression analysis revealed a high correlation between the average values of Cmax in saliva and plasma both in the patient (r=0.96) and healthy volunteer group (r=0.98). CONCLUSIONS: With statistically significant differences in the areas under pharmacokinetic curves in blood plasma and saliva, the remaining pharmacokinetic parameters of saliva and blood plasma did not significantly differ between patients with CAP and healthy volunteers. A significant direct correlation was revealed between the mean concentration and pharmacokinetic parameters in saliva and blood plasma in both groups. The study demonstrated the possibility of using saliva as a biomaterial in the study of levofloxacin pharmacokinetics.
BACKGROUND: Levofloxacin concentrations do not always reach desired levels when administered at a standard dose; therefore, measuring levofloxacin levels in the blood plasma or other alternative matrices, such as the saliva, can help clinicians make informed decisions concerning the dosage and mode of administration. Saliva, as an object of research, is of particular interest due to the simplicity and non-invasiveness of sampling for analysis. AIM: This study aimed to determine the comparative pharmacokinetics of levofloxacin in the blood plasma and saliva of patients with community-acquired pneumonia (CAP) and assess the possibility of using saliva as an alternative sampling matrix in pharmacokinetic studies. MATERIALS AND METHODS: Levofloxacin concentration in the blood plasma and saliva of patients with CAP and volunteers was determined using high-performance liquid chromatography on an Agilent 1200 liquid chromatography (Agilent, USA) with an ultraviolet detector. Sample preparation of bioassays was performed using protein precipitation. Patients and volunteers took 1 tablet (500 mg dose) of levofloxacin per os in the morning, on an empty stomach. Blood and saliva samples were taken at the initial blood sample and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after taking the drug. The pharmacokinetic parameters were determined, namely Cmax as the peak concentration of the drug; Тmax as the time-to-peak concentration; AUC0t as the area under the pharmacokinetic curve in the range from 0 to the last experimental point on the curve; AUC0 as the total area under the pharmacokinetic curve from zero to infinity; t1/2 as half-life period; MRT as mean residence time of the drug in the blood (h); Cl/F as clearance; and Vss/F as the total distribution volume. RESULTS: The maximum blood plasma and saliva concentration of patients was reached 1 h after taking the drug and amounted to Сmax=5.982.89 g/ml and Сmax=4.413.83 g/ml, respectively. Additionally, the maximum concentrations in blood plasma and saliva were recorded 1 h after taking the drug as 5.523.07 g/ml and 3.250.85 g/ml, respectively, in healthy volunteers. The correlation coefficient (r) between the mean values of the levofloxacin concentrations in the blood plasma and the saliva of patients with CAP was 0.953 and that of healthy volunteers was 0.977. DISCUSSION: Pharmacokinetic parameters were calculated based on blood plasma and saliva concentrations. Their comparative analysis revealed almost the same absorption rate from the gastrointestinal tract in patients and healthy volunteers. Correlation-regression analysis revealed a high correlation between the average values of Cmax in saliva and plasma both in the patient (r=0.96) and healthy volunteer group (r=0.98). CONCLUSIONS: With statistically significant differences in the areas under pharmacokinetic curves in blood plasma and saliva, the remaining pharmacokinetic parameters of saliva and blood plasma did not significantly differ between patients with CAP and healthy volunteers. A significant direct correlation was revealed between the mean concentration and pharmacokinetic parameters in saliva and blood plasma in both groups. The study demonstrated the possibility of using saliva as a biomaterial in the study of levofloxacin pharmacokinetics.
Antibacterials can have nephrotoxic effects because medicinal products of this class are primarily excreted by the kidneys. The aim of the study was to analyse literature data on the mechanisms, risk factors and specific features of toxic nephropathy development during antibiotic therapy. The article considers mechanisms of development of acute interstitial nephritis, acute tubular necrosis, crystal deposits in the tubules, proximal or distal tubulopathy with electrolyte abnormalities during the use of antibiotics. Nephrotoxicity was shown to be most often associated with the use of aminoglycosides, beta-lactams, and vancomycin. The authors analysed the dependence of nephrotoxicity on antibacterial agent lipophilicity and drug-drug interactions. The main risk factors for developing nephropathy are older age; male sex; black race; hypovolemia; arterial hypotension; angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, non-steroidal anti-inflammatory drugs or their combinations; and individual genetic characteristics. Nephrotoxicity is associated with genetic characteristics of the systems responsible for metabolism and excretion of antibacterial products: cytochrome P450 isoenzymes, P-glycoprotein, multidrug resistance protein (MRP), multidrug and toxin extrusion (MATE), breast cancer resistance protein (BCRP), and organic anion transporters. Severe generalised infections change pharmacokinetic parameters of antibacterial products. This should be taken into account when prescribing the hydrophilic antibiotics that are excreted by tubular secretion and reabsorbed in the renal tubules. The study demonstrated the effectiveness of the method comprising a combination of dose adjustment based on therapeutic drug monitoring results and renal function monitoring for improving the safety of antibiotic therapy.
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