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Indian Journal of Pharmacology, Vol. 38, No. 5, September-October, 2006, pp. 368-369 Research Letter Pharmacokinetics of single intravenous bolus dose of ofloxacin in calves Mohan A, Garg SK Department of Pharmacology & Toxicology, College of Veterinary Science & Animal Husbandry, U.P. Pt. Deen Dayal Upadhyaya Veterinary Science University, Mathura-281 001 Code Number: ph06105 The synthetic bactericidal agents, fluoroquinolones, have revolutionised treatment both in human and veterinary medicine. They are effective against bacterial pathogens resistant to most of the conventional antibacterials and possess excellent antibacterial activity at very low concentrations.[1] Ofloxacin, a new generation fluoroquinolone, is highly effective against gram-negative and gram-positive bacteria, Mycoplasma, Rickettsiae, Chlamydia, and Mycobacterium species.[1] Pharmacokinetic data of ofloxacin are available for dogs,[2] pigs,[3] and neonatal calves.[4],[5] In view of the age-dependent differences in pharmacokinetic behaviour of drugs and the paucity of such data on cow calves, the present disposition kinetics study was undertaken following a single intravenous bolus dose administration. This was done to compute/suggest the rational dosage regimen of ofloxacin for female calves. Five apparently healthy, female, Hariana crossbred calves (6 to 11 months) weighing 43 to 73 kg, were procured from the animal farm of our institute. The animals were offered ad libitum green fodder and drinking water. Five per cent (w/v) stock solution of ofloxacin base (Ranbaxy Research Laboratories, Gurgaon, India) was prepared by dissolving the drug in 0.1 N hydrochloric acid, and the pH was adjusted to 7.4. The stock solution was further diluted to 3 % (v/v) with sterile water before injection at a dose of 5 mg/kg body weight into the external jugular vein. Blood samples were collected into heparinised test tubes from the catheterised jugular vein at 0.04, 0.08, 0.16, 0.25, 0.50, 0.75, 1.0, 1.5, 2, 3, 6, 9, 12, 24, 36, 48, 60, and 72 h post-drug administration. Plasma was separated and stored at -20o C till analysis within 3 to 5 days of sample collection. Plasma ofloxacin concentrations were determined by fluorimetric method of Gurumurthy et al .[6] Standard curve exhibited linearity in the concentration range of 0.25 to 10.0 µg/ml. Minimum sensitivity of the assay method was 0.25 µg/ml. The overall recovery was 95.67 + 0.96% (93.81 to 99.0%) and the coefficient of variation was 7.53 + 2.38%. The data of ofloxacin plasma concentration versus time of individual animals were subjected to visual method of curve fitting and best described by biexponential equation.[7] From the constants so derived, other pharmacokinetic parameters were calculated and expressed as mean + SEM, except the half life, which was expressed as harmonic mean values. Following single intravenous injection of ofloxacin (5 mg/kg), plasma concentration was 7.28 + 0.49 µg.ml-[1] at 2.5 min. This initially declined rapidly and, thereafter, gradually to 0.53 + 0.06 µg.ml -1 at 6 h. [Figure - 1] Evaluation of the semi-log plot of plasma ofloxacin concentration-time data indicated two-compartmental pharmacokinetic behaviour in calves as in neonatal calves.[4] The distribution (t 1/2a) and elimination half life (t 1/2b) values of ofloxacin in calves after a single i.v. administration were found to be 0.12 and 2.21 h, respectively. [Table - 1] The apparent volume of distribution (Vdarea), area under the curve (AUC) and total body clearance (ClB) were calculated to be 1.40 + 0.14 Lkg -1, 12.00 + 0.90 µg.ml -1.h and 430.04+42.96 ml.kg -1 h -1, respectively. [Table - 1] Distribution half life of 0.12 h following i.v. administration suggests its rapid distribution into body tissues and fluids of calves. Elimination half life of ofloxacin in calves in the present study was 2.21 h. A high Vdarea of 1.40 + 0.40 Lkg -1 indicated wide distribution of ofloxacin into body tissues and fluids. The ratio of transfer rate constants of the drug from the central to the peripheral compartment and vice versa (K 12 /K 21 ; 1.15 + 0.27) also indicates that ofloxacin is widely distributed to peripheral tissues. It does not, however, seem to be appreciably retained there as reflected by the calculated value of T/P (1.36 + 0.33). High values of Vdarea of ofloxacin have also been reported in pigs[3] and neonatal calves.[4] The total body clearance value reflects the overall efficiency of body to eliminate any xenobiotic from the body. The ClB of ofloxacin in calves (430.04 + 42.96 ml kg -1sub h -1) was much higher compared with that in neonatal calves.[4] This may be res-ponsible for the shorter half life in calves than neonatal calves.[4] Fluoroquinolones exert concentration-dependent killing, and to maximise the clinical efficacy of antibacterial agents it is important to obtain the plasma Cmax to MIC ratio of 8-12 and AUC to MIC ratio value of> 100 to 1.[8] Further bacterial regrowth due to resistant-subpopulations can be prevented when peak concentrations exceed the MIC value of the pathogen by a factor of 8 or more.[8] The MIC of ofloxacin against most of the susceptible microorganisms ranges between 0.05 and 2.5 µg/ml.[1] Considering the MIC as 0.5 µg/ml against most of common animal pathogens,[1] the value of Cmax/MIC in the present study was found to be 14.56. AUC/MIC value was, however, much less (only 24). Despite this, because of the concentration-dependent killing effect and post-antibiotic effects of fluoroquinolones and Cmax/MIC value of 14.56 in the present study, it may not be unreasonable to suggest that ofloxacin be administered to female calves at 24 h interval by intravenous route. Against more severe infections with resistant microbes, however, higher plasma concentrations (>1.0 mg.ml -1) may be required. Accordingly, the dosage regimens may be computed using the disposition kinetic data obtained from female calves and the MIC values against specific invading microorganisms. References
Copyright 2006 - Indian Journal of Pharmacology The following images related to this document are available:Photo images[ph06105t1.jpg] [ph06105f1.jpg] |
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