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Abstract
Levofloxacin pharmacokinetic profiles were evaluated in 6 healthy female rabbits after intravenous (I/V), intramuscular (I/M), or subcutaneous (S/C) administration routes at a single dose of 5 mg/kg in a 3 × 3 cross-over study. Plasma levofloxacin concentrations were detected using a validated Ultra Performance Liquid Chromatography method with a fluorescence detector. Levofloxacin was quantifiable up to 10 h post-drug administration. Mean AUC0-last values of 9.03 ± 2.66, 9.07 ± 1.80, and 9.28 ± 1.56 mg/h*L were obtained via I/V, I/M, and S/C, respectively. Plasma clearance was 0.6 mL/g*h after I/V administration. Peak plasma concentrations using the I/M and S/C routes were 3.33 ± 0.39 and 2.91 ± 0.56 µg/mL. Bioavailability values, after extravascular administration were complete, – 105% ± 27% (I/M) and 118% ± 40% (S/C). Average extraction ratio of levofloxacin after I/V administration was 7%. Additionally, levofloxacin administration effects on tear production and osmolarity were evaluated. Tear osmolarity decreased within 48 h post-drug administration. All 3 levofloxacin administration routes produced similar pharmacokinetic profiles. The studied dose is unlikely to be effective in rabbits; however, it was calculated that a daily dose of 29 mg/kg appears effective for I/V administration for pathogens with MIC < 0.5 µg/mL.
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Fig. 1.
Semilogarithmic plots of average levofloxacin plasma concentrations in rabbits (error bars represent standard deviations) after I/V (n = 6), I/M (n = 6), and S/C (n = 4) levofloxacin administration of 5 mg/kg bodyweight. I/V, intravenous; I/M, intramuscular; S/C, subcutaneous.
Fig. 2.
Changes in tear osmolarity in rabbits after a single 5 mg/kg levofloxacin dose administered via I/V (n = 6), I/M (n = 6), or S/C (n = 4) routes (mean values indicated; error bars represent standard deviation). I/V, intravenous; I/M, intramuscular; S/C, subcutaneous.
Table 1.
Mean (± SD) pharmacokinetic parameters of levofloxacin in plasma following I/V, I/M or S/C administration to rabbits at a dose of 5 mg/kg bodyweight
| PK parameters | Units | I/V (n = 6) | I/M (n = 6) | S/C (n = 4) |
|---|---|---|---|---|
| AUC0−last | mg* h/L | 9.03 ± 2.66 | 9.07 ± 1.80 | 9.28 ± 1.56 |
| AUC0−inf | * mg* h/L | 9.08 ± 2.64 | 9.07 ± 1.80 | 9.31 ± 1.50 |
| AUMC0−last | * mg* h* h/L | 22.93 ± 12.46 | 37.87 ± 18.35* | 36.62 ± 17.35 |
| AUMC0−inf | mg* h* h/L | 23.64 ± 12.17 | 37.89 ± 18.34* | 36.98 ± 16.82 |
| C max | μ g/mL | N/A | 3.33 ± 0.39 | 2.91 ± 0.56 |
| C first | μ g/mL | 7.13 ± 1.47 | N/A | N/A |
| t max MEDIAN | h | N/A | 0.50 (0.08–0.75)† | 0.75 |
| t1/2λ z HM | h | 2.06 ± 0.18 | 2.01 ± 0.24 | 1.80 ± 0.14 |
| λ z | 1/h | 0.34 ± 0.03 | 0.34 ± 0.04 | 0.39 ± 0.03 |
| MRT0−last HM | h | 2.19 ± 0.83 | 3.75 ± 1.16* | 3.44 ± 1.31 |
| MRT0−inf HM | h | 2.27 ± 0.80 | 3.75 ± 1.16* | 3.52 ± 1.25 |
| MAT HM | h | N/A | 1.29 ± 0.61 | 0.45 ± 1.47 |
| Cl | mL/g* h | 0.60 ± 0.18 | N/A | N/A |
| Cl/F | mL/g* h | N/A | 0.57 ± 0.11 | 0.55 ± 0.10 |
| V ss | mL/g | 1.37 ± 0.39 | N/A | N/A |
| V area/F | mL/g | N/A | 1.66 ± 0.34 | 1.42 ± 0.18 |
| F | % | N/A | 105.69 ± 27.50 | 118.93 ± 40.51 |
PK, pharmacokinetic; AUC0−last, area under the plasma-concentration time curve from zero to the last quantified sampling point time; AUC0-inf, area under the plasma-concentration time curve from zero extrapolated to infinity; AUMC0−last, area under the first moment curve from zero to the last quantified sampling point time; AUMC0−inf, area under the first moment curve from zero extrapolated to infinity; C max, maximum plasma drug concentration; C first, concentration at first sample collection point; t max, time of the maximum plasma concentration; t1/2λ z, half-life of the elimination part of the curve; λ z, slope of the elimination part of the curve; MRT0−last, mean residence time from zero to the last quantified sampling point time; MRT0−inf, mean residence time from zero extrapolated to infinity; MAT, mean absorption time; Cl, total plasma clearance; Cl/F, plasma clearance corrected to the bioavailability; V ss, volume of distribution at steady-state; V area/F, volume of distribution corrected to the bioavailability; n, number of experimental animals receiving levofloxacin via the corresponding route of administration; I/V, intravenous; I/M, intramuscular; S/C, subcutaneous; N/A, not applicable; HM, harmonic mean.* Significantly different from I/V administration (p < 0.05);
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