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Indian Journal of Pharmacology, Vol. 38, No. 5, September-October, 2006, pp. 366-367 Research Letter Milk kinetics of gatifloxacin after single dose intravenous administration in healthy and febrile goats Verma DK, Roy BK Department of Pharmacology and Toxicology, Ranchi Veterinary College, Birsa Agricultural University, Kanke, Ranchi -834006 Code Number: ph06104 Fluoroquinolones are broad spectrum antimicrobial agents. They are used extensively in animals to combat mammary gland infections. Gatifloxacin possess low resistance problem, fewer side effects and better coverage of gram negative and gram positive bacteria including anaerobes, mycoplasma, chlamydia, legionella and mycobacteria. In addition its bioavailability, half-life and peak plasma concentrations are greater when compared to other quinolones. Pharmacokinetics of drugs in milk has been studied in goats[1] as well as buffalos.[2] Pharmacokinetics of gatifloxacin has been investigated in healthy humans.[3] There is paucity of reference material on the milk kinetics of this antimicrobial in lactating animals. Therefore, the present work was undertaken to explore the milk kinetics in lactating goats. The study was conducted on six clinically healthy, lactating Black Bengal goats. They weighed between 14 to 20 kg and offered a milk yield of 250 to 400 ml per day. Gatrim ® infusion (10 mg/ml gatifloxacin in dextrose base) marketed by Nicholas Piramal, India Ltd, Mumbai was injected i.v. at the dose of 5 mg/kg, body weight into each of the six goats. The animals were housed in the departmental animal shed and were allowed fodder and routine grazing. Water was given ad libitum. Fever model was constructed after i.v. (0.2 µg/kg) administration of lipopolysaccharides (LPS) of E. coli [4] in each of the six goats. Gatifloxacin (GTX) was administered i.v. (5 mg/kg, b.w.) in both healthy and febrile goats. Half dose of LPS was again injected at fifth hour to maintain the fever till 12 h. Milk samples were collected in sterile vials at 2.5, 5, 10, 20, 30 and 45 min and 1, 2, 3, 4, 6, 8, 10 and 12 h after i.v. administration of drug. After 15 days of washout interval, the same group of goats was used for another sample collection. The GTX concentrations in milk samples were estimated using a U.V. Spectrophotometer.[5] One ml of milk was mixed with 4 ml of 0.02% isopropyl alcohol in formic acid. This mixture was shaken vigorously and centrifuged at 3000 rpm for 15 min. The clear supernatant was transferred to another test tube and analysed against the standard curve of GTX in milk of different concentrations plotted for each set of sample. The sensitivity of the method was 0.62 µg/ml. The pharmacokinetic parameters were calculated using a computer software (Pharmkit). Statistical analysis was done using paired 't' test to compare the healthy and the febrile goats. P < 0.05 was considered significant. The maximum milk concentration of GTX in healthy and febrile goats after single dose i.v., administration was 38.97±0.59 µg/ml at 45 min and 6.10±0.32 µg/ml at 20 min, respectively. [Figure - 1] The different pharmacokinetic profiles of GTX in milk have been depicted in [Table - 1]. The t½ ®in healthy and febrile goats was 2.47±0.08 and 1.66±0.10 h respectively. The mean value of ClB and Vdarea were 0.66±0.22 ml/kg/min and 0.14±0.006 L/kg, respectively, in healthy goats. In febrile goats the mean value of the above parameters were 7.97±0.57 ml/kg/min and 1.13±0.08 L/kg respectively. The excretion of drugs through milk is one of the most important routes in lactating animals. Many drugs passively diffuse through the mammary gland to achieve higher concentration in milk following pH partition hypothesis.[6] The passive diffusion of drugs is an advantage because such drugs may be employed to combat mammary gland infections, especially in animals suffering from mastitis. Therefore, the mammary excretion of drugs assumes significance both from the standpoint of clinical applications and public health hazard problems. The milk concentrations of GTX in healthy goats were significantly ( P < 0.01) higher compared with febrile goats. The observed finding may have been due to the decreased blood flow in febrile goats. This was caused by vasoconstriction due to initial "chilling" phase that, in turn, caused shivering.[7] The vasoconstriction, therefore, possibly reduced the passage of GTX across the gland membrane into the gland acini. A similar finding has been noted after i.v., administration of cefazoline.[7] The Cmmax in healthy goats was higher due to passive diffusion of GTX from blood (pH 7.4) to milk (pH 6.8) after crossing the plasma milk barrier. The degree of ionisation of GTX (pH 9.2) is supposed to be higher in milk due to the acidic nature of milk.[8] The Cmther of GTX in the above range of MIC (0.1 to 2 µg/ml) for all susceptible microorganisms was maintained till 12 h and 6 h in healthy and febrile goats respectively after i.v., administration. It may be explained here that the drug was highly ionised and rapidly excreted through milk in febrile condition. The above findings are strengthened by relative kinetic parameter, ClB, which was found to be lower in healthy (0.66±0.02 ml/kg/min) compared with febrile goats (7.97±0.57 ml/kg/min). [Table - 1] It is evident from [Figure - 1] that tCmmax of gatifloxacin in febrile goats (20 min) occured earlier than that in healthy goats (45 min) after i.v., administration. The findings of this study are in accordance with the earlier observation[7] indicating variation in normal and febrile goats in the rate of passage of drugs. This is beneficial in mammary gland infections associated with fever. On the basis of milk level time profile, the suggested dosage regimen of GTX calculated using an already reported method[9],[10] is 0.16 to 5.45 mg/kg, i.v. 12 h in healthy goats. In febrile goats the same was found to be 0.36 to 6.89 mg/kg, 6 h. References
Copyright 2006 - Indian Journal of Pharmacology The following images related to this document are available:Photo images[ph06104f1.jpg] [ph06104t1.jpg] |
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