Norfloxacin pharmacokinetics in lactating cows with sub-clinical and clinical mastitis

Abstract

Single-dose pharmacokinetics of norfloxacin after intravenous administration of norfloxacin nicotinate at 10 mg norfloxacin/kg body weight was investigated in cows with healthy udders and in cows with chronic subclinical and postacute clinical mastitis. An HPLC method was used to determine the norfloxacin concentrations in serum and milk. Significant differences were observed in norfloxacin pharmacokinetics when administered to cows with infected udder quarters. The clearance (Cl) values were 10.4 ± 2.5, 13.2 ± 1.9 and 14.2 ± 2.1 mL/min/kg (mean ± SD) in the control (healthy udder) cows and in cows with subclinical and postacute clinical mastitis, respectively. There appeared to be a trend of increasing clearance according to severity of the disease. The volume of distribution at steady state (V(ss)) in the respective groups was 3.1 ± 0.7, 2.2 ± 0.6 and 1.3 ± 0.2 L/kg. The volume of distribution was significantly decreased in the cows with postacute clinical mastitis. The half-lives (t(1/2)) and mean residence times (MRT) of norfloxacin were 353, 206 and 115 min (harmonic means) and 306 ± 76, 168 ± 39 and 95 ± 9 min in control cows or in cows with subclinical and postacute clinical mastitis, respectively. The half-lives in the clinical mastitis group were significantly shorter than in the control group and the mean residence times were significantly shorter in the two mastitis groups when compared to the control group. Norfloxacin concentrations in milk were extremely high when compared to the respective serum concentrations. The area under the concentration vs. time curve (AUC) of norfloxacin in milk was 23,899 ± 6206 mg/L x min in the control cow group. The AUC in milk was significantly lower in the infected udder quarters of the mastitis groups (5075 ± 1887 mg/L x min and 7484 ± 4645 mg/L x min in the subclinical and the clinical group). The AUC values were significantly lower in milk from the infected udder quarters of the cows with chronic subclinical and postacute clinical mastitis when compared to the values in milk from the healthy quarters of the same udder. Norfloxacin was marginally bound to serum protein. The binding was concentration dependent and was 19, 13 and 6% at 0.2, 1.0 and 8.4 mg/L, respectively. Binding to milk protein was 46-51% and concentration independent. An in vitro dialysis model was used to simulate drug transport between serum and milk as a function of protein binding. The results showed that the rate of norfloxacin disposition from milk to serum was slower than from serum to milk, which was in agreement with the findings obtained in the pharmacokinetic study. Norfloxacin was poorly soluble in organic solvents and our results suggest that changes in the degree of ionization of the drug in different body fluids considerably affect its disposition.