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DISPOSITION KINETICS OF CIPROFLOXACIN IN NORMAL RABBITS AND CHANGES OBSERVED IN INDUCED DIABETIC CONDITION.

Byline: S. Bashir, Alamgeer, M. Akram, M. N. Qaisar and H. M. Irfan

ABSTRACT: The pharmacokinetic parameters of ciprofloxacin were determined following oral administration of a single dose of 20mg/kg body weight in normal rabbits and these changes were observed in experimentally induced diabetic rabbits. High performance liquid chromatographic method was employed for the estimation of ciprofloxacin in plasma samples. A significant (Pless than0.05) decrease in drug plasma concentration was recorded at 0.17, 0.33,1.0, and 8.0 hrs sampling times, and highly significant (Pless than0.01) decrease of drug concentrations was observed at 0.67 and 12.0 hr in diabetic rabbits, except sampling at 1.50, 2.00, and 4.0 hrs which did not reveal any difference of plasma levels between normal and diabetic rabbits. A highly significant (Pless than0.01) increase in elimination rate constant (83%), and significant (Pless than0.05) increase in absorption rate constant (16.98%), Cmax (calc) (45.83%), and Clearance (15.21%) in diabetic rabbits as compared to the normal animals were observed.

Absorption half life, Distributionrate constant, Distribution half life, Elimination half life, AUC(0-t) , AUC(0-[?]), and MRT, decreased (Pless than0.05) significantly in diabetic rabbits.. The results reflect a need for an adjustment of dose and dosage regimen under diabetic condition.

Key words: "Diabetic, pharmacokinetic parameters, ciprofloxacin, rabbits.

INTRODUCTION

Since the flouroquinolones especially ciprofloxacin are often prescribed to treat poly microbial infection in diabetes like diabetic gastro paresis, diabetic foot infection and respiratory infection (Hammerman, 2003).

At present practice guide line dictate that most physicians would not initiate oral antimicrobial therapy, yet would use them to complete treatment after initial patient improvement. This lack of confidence in oral antibiotic as first line agent has probably been secondary to the limited availability of information of the effect of diabetes on the pharmacokinetic of orally administered antibiotics.

Diabetes is a disorder arising from a deficiency in insulin secretion and excess glucagons secretion from the pancreas. The other causes are pancreatitis, trauma stress, neurogenic changes, infection and hormonal changes. Clinically, diabetes mellitus is characterized by polyurea, glycosuria, hyperglycemia, polyphagia, ketosis, loss of weight and weakness (Lehninger et al, 1975).

Diabetes can be produce readily in different animals by chemical or surgical methods. Alloxan and streptozotocin are the most extensively used chemical agents in animal models to produce diabetes. Alloxan (meso-xylylurea) acts by selectively destroying the beta cell without affecting alpha cells of islets of langerhan's, thus resulting in hyper glycemia and ketoacedosis, moreover alloxan diabetes of varying degree of severity is accompanied by increased cholesterol and triglyceride levels. Nawaz and coworkers investigated the disposition kinetics and urinary excretion of sulphadimidine in normal and alloxan treated dogs and found significant difference between the two groups (Nawaz et al., 1982). Ahmad et al 1995 have investigated the effect of experimentally induced diabetes on the pharmacokinetic and bioavailability of erythromycin in rabbits.

All of these studies suggest that the diabetic state influences the bioavailability and disposition kinetics of drug. The biodisposition of ciprofloxacin is likely to be affected in altered biochemical environment of the body during diabetes.

The present study therefore was design to estimate the disposition kinetics of ciprofloxacin a commonly used antibiotic in normal and alloxan induced diabetic rabbits.

Ciprofloxacin is a flouroquinolone derivative with outstanding antibacterial activity against gram negative and some gram positive bacteria as well as on some Chlamydia and mycoplasma, and many mycobacterium species (Neu, 1987; Campoli-Richards et al., 1987; Hyatt et al., 1994).

Its action takes place via the inhibition of the bacterial DNA gyrase topoisomerase IV which are essential enzyme for DNA replication and synthesis. In animals Quinolones especially exhibit favorable pharmacokinetic properties, their apparent volume of distribution suggested substantial tissue penetration (Abd El-Aty et al., 2005; Albarellos et al., 2004).

MATERIALS AND METHODS

Animals: Twelve healthy white albino rabbits of either sex obtained from Veterinary University Lahore ranging in body weight from 1.25-1.8 kg were used.

All the animals were maintained under similar feeding and managemental conditions in animal house of University College of Pharmacy, University of the Punjab, Lahore and checked periodically by a veterinary doctor before and during the experiment. The animals were fed twice daily with fresh green fodder and black gram in the morning and evening after checking for any contamination, while water was provided ad-libitum.

Protocol of study: Pharmacokinetics of ciprofloxacin was studied after administration of an oral dose in normal and diabetic rabbits. The diabetic condition was produced in the normal rabbits during a wash out period of 10 days.

Diabetic condition: Diabetes was induced by injecting 1% solution of alloxan in normal saline at the dose level of 120mg/kg body weight in divided doses of 20-30mg/day for 3- 4 consecutive days . After the injection of alloxan blood glucose level of each rabbit was measured daily in the morning and evening, until the blood glucose level was found to exceed 300mg/dl, the figure regarded as hyperglycemic (Ahmad et al., 1997).

Drug Administration: For the determination of pharmacokinetics of ciprofloxacin in normal and diabetic rabbits, Ciprofloxacin tablet (Bayer) was dissolved in distilled water and administered as a single dose of 20mg/kg of body weight orally with the help of a feeding needle attached to a 10ml syringe.

Sampling Procedure: The blood samples (2ml) were collected through the juggler vein of the rabbits, which were held in wooden cages, in heparinized glass centrifuge tubes with the aid of sterilized disposable plastic syringes just before and at 0.17, 0.33, 0.67, 1.00, 1.50, 2.00, 4.00, 8.00, and 12.00 hrs after the drug administration in normal rabbits and after the induction of diabetes in the same rabbits. The blood samples were centrifuged at 3000 rpm for 10 minutes to separate the plasma for analysis.

Drug analysis: The concentration of ciprofloxacin in plasma was determined by the high performance liquid chromatographic procedure as described by Bashir et al., (2008). Estimation of concentration was carried out by interpolating ciprofloxacin peak areas on a calibration curve of spiked the blank plasma over the range assayed.

Sample preparation: After separating the plasma from blood sample, an equal amount of 5% perchloric acid was added to all tubes for protein precipitation, tubes were vortexed for two minutes and centrifuge at 2000 rpm for 10 minutes. The aliquots was separated for injecting into the HPLC system( Agilent 1100 series with vacuum, Quaternary pump, Auto sampler 10v, Thermostated column compartment, Variable wave length detector) and a column(Zorbex Eclipse x DB C18 Analytical 4.6 x 150mm - 5u).

Pharmacokinetic Analysis: Pharmacokinetic analysis was performed by non compartmental approach along with compartmental approach as well; using two compartment models (Raina et al., 2008) by a soft wear Pharmacolysis(r) (Ahmad, 2006).

Statistical analysis: All values are expressed as the mean +- of standard deviation (SD) of twelve animals. The pharmacokinetic parameters obtained for the normal and diabetic rabbits, after a single oral dose of 20mg/Kg body weight were compared using a Paired t test, considering a probability of (Pless than 0.05) to be significant

RESULTS AND DISCUSSION

Ciprofloxacin Plasma Concentration -Time Profile:

Plasma concentrations of ciprofloxacin (20mg/kg orally) in normal and diabetic rabbits are presented in Table 1 and figure 1, shows the mean plasma concentration versus time profile. The maximum plasma concentration of 0.860 +- .01ug/ml and 0.770 +-.01ug/ml were attained in normal and diabetic rabbit respectively at, 0.67 hours after drug administration [10]. A significant (Pless than0.05) decrease in drug concentration was observed at sampling time 0.17, 0.33, 1.0 and 8.0 hour in diabetic rabbits. Where as a highly significant (Pless than0.01) decrease occurred at the sampling time of 0.67 and 12.0 hour in diabetic rabbits. At the sampling time of 1.5, 2.0, and 4.0 hour, no significant difference was observed. The lower concentration in the alloxinized rabbits may be attributed to the increased protein binding of the drug. The other reason for lowered plasma concentration may be reduced absorption of drug from gastrointestinal tract.

These finding are also supported by the similar type of studies conducted in rabbits using d fferent drugs in past (Iqbal et al., 1989; Ahmad et al., 1997; Qamar et al., 1997.

Pharmacokinetics of Ciprofloxacin in Normal and Diabetic Rabbits: Pharmacokinetic parameters of ciprofloxacin after oral administration at a dose level of 20mg/kg body weight in normal and alloxan induced rabbits have been presented in Table 2. It may be seen that a lower peak plasma concentration is achieved in diabetic animals as compared to normal rabbits.

It is clear from the data that highly significant decrease in AUC (0-t), AUC (0-[?]) and absorption half life occurred between the normal and diabetic rabbits, where as elimination rate constant, absorption rate constant were increased, and distribution half life and elimination half life decreased significantly.

The mean +- SEM value for absorption rate constant was 4.18+- 0.26 hours-1 and 4.89 +- 0.27 hours-1 and value of absorption half life 0.17+- 0.01 hours and 0.15 +- 0.01 hours in normal and diabetic rabbits respectively. A lower absorption half life value in the diabetic rabbits suggest quick absorption of the drug, where as the value for elimination rate constant increased significantly in the diabetic rabbit that is (83.33%) resulted in a shorter elimination half life i.e. 7.16 +- 0.97 hours.

These results are similar which have been described by the finding of Qamar et al., (1997).

Table- 1 [Mean+- SEM (n=12)] Plasma Levels Vs Time of ciprofloxacin in normal and diabetic state following oral administration of a single dose of 20mg/Kg body weight.

###Group###Paired###

Time (hours)###Normal###Diabetic###Ratio###% age Difference###

###mg/m###mg/ml###t- test###

0.17###0.680 +- .01###0.60 +- .02###1.13###-13.33###**###

0.33###0.803 +- .02###0.699 +-.02###1.15###-14.88###**###

0.67###0.860 +- .01###0.770 +- .01###1.12###-11.69###***###

1.00###0.709 +- .02###0.662 +- .02###1.07###-7.10###**###

1.50###0.621 +- .01###0.601 +- .02###1.03###-3.33###ns###

2.00###0.453 +- .01###0.440 +- .02###1.03###-2.95###ns###

4.00###0.322 +- .01###0.330 +- .02###0.98###+2.42###ns###

8.00###0.230 +- .02###0.159 +- .02###1.45###-44.65###***###

12.00###0.181 +- .02###0.105 +- .01###1.72###-72.38

***

ns = non- significant difference ** = significant difference (P less than 0.05)

*** = highly significant difference (P less than 0.01) = decrease + = increase

Table- 2. [Mean +- SEM (n=12)] Pharmacokinetic parameters of ciprofloxacin in rabbits following a single oral dose of 20 mg/kg body weight in normal and diabetic state.

###Parameters###Normal###Diabetic###Ratio###% Diff.###Paired###

###t-test###

Absorption Rate Constant[hr-1]###4.18+- 0.26###4.89 +- 0.27###0.85###+16.98###**###

Absorption Half-Life[hr]###0.17+- 0.01###0.15 +- 0.01###1.13###-11.76###**###

Distribution Rate Constant [hr-1]###1.08+- 0.10###0.69 +- 0.13###1.56###-36.11###**###

Distribution Half-Life [hr]###1.26+- 0.06###0.69 +- 0.13###1.82###-45.23###**###

Elimination Rate Constant [hr-1]###0.06+- 0.00###0.11 +- 0.01###0.54###+83.33###***###

Elimination Half-Life [hr]###10.98+- 0.45###7.16 +- 0.97###1.53###-34.79###**###

AUC (0-t) (Obs Area) [hr.mg.l-1]###3.96+- 0.05###3.44 +- 0.07###1.15###-13.13###***###

AUC (0-inf.) (area) [hr.mg.l-1]###6.85+- 0.23###4.53 +- 0.13###1.51###-33.86###***###

MRT (area) [hr]###4.47+- 0.04###3.95 +- 0.03###1.13###-11.63###***###

C (max) (observed) [mg.l-1]###0.86+- 0.01###0.77 +- 0.01###1.11###-10.46###**###

T (max) (observed) [hr]###0.67+- 0.00###0. +- 0.00###0.00###0.00###ns###

Lag Time [hr]###0.3+- 0.05###0.1 +- 0.02###3.00###-66.66###**###

Cl (area) /kg [l.hr-1]###5.06+- 0.07###5.83+- 0.12###0.86###+15.21###**

** = significant difference (P less than 0.05) *** = highly significant difference (P less than 0.01) = decrease + = increase

Similarly MRT value in diabetic rabbits decreased significantly over the value of normal animals. A significant (Pless than0.05) increase in total body clearance of ciprofloxacin was achieved in the alloxan treated rabbits (5.83+-0.12 l h-1) as compared to normal rabbits (5.06+-0.07). Excessive and increased urination may be the possible reason for the increased body clearance in diabetes. These results are in line with previous observation in diabetic rabbits and dogs (Nawaz et al., 1982; Qamar et al., 1997). In the alloxinized rabbits, a decrease in blood pH is favorable for the unionization of the drug. The unionized drug can easily cross the bio-membranes of drug eliminating organs, also change in pH causes conjugation of drug, which can easily cross the drug-eliminating organ.

Assuming non-significantalteration in urine pH, the higher flow of urine prevented any possible back diffusion and resulted higher total body clearance. It is found from the result that diabetes has a significant effect on disposition kinetics of ciprofloxacin in rabbits. The present findings shows the value for elimination rate constant was significantly (P< 0.05) lower in diabetic condition. a significantly (P< 0.05) lower total body clearance in alloxan animal may be due to the lower value of K-terminal.

The present study shows that the metabolic changes in the alloxan induced diabetes after oral administration of ciprofloxacin changes the disposition kinetics that initiate the need for an adjustment of dosage regimen under this condition.

The clinical implication of the present finding have to await clarification and verification in investigation performed in real diabetic condition.

Time (h)

REFERENCES

Abd El-Aty, A. M., A, Goudah, M. Ismail and M Shimoda (2005). Disposition kinetics of difloxacin in rabbit after intravenous and intramuscular injection of DicuralVet.

Res.Commun., 29 (4): 297-304.

Ahmad, M., M Nawaz., M. Jamshaid and M. T. J Khan.. (1995). Bioavailability and disposition kinetics of ertromycin in normal and metabolically altered rabbits following oral administration.Pak. J .Pharm. Pb. Univ Lhr., 8 (2) 31- 35.

Ahmad, M., R. Nawaz and M. Nawaz (1997). Disposition kinetics of erythromycin after intravenous administration in normal and alloxan diabetic rabbits. Pak Vet J., 17 (1): 35-39.

Ahmad, T., (2006). "Pharmacolysis," Pharmacokinetic software Pk IV (computer program): M.S. version. Pharma Professional Services, Karachi, Pakistan

Albarellos, G. A., V. E. Kreil and M. F. Landoni (2004). Pharmacokinetics of ciprofloxacin after single intravenous and repeat oral administration to cats. J. Vet. Pharmacol Ther., 27 (3): 155-62.

Bashir, S., M. Jamsaid, B. Ahmed and J. Iqbal. (2008). Pharmacokinetics of ciprofloxacin in normal rabbits and changes observed in Induced dehydrated condition. Pak J Pharm Sci., 21 (31) 225-9.

Campoli-Richards, D. M., J. P. Monk., A. Price, P Benfield., P. A. Todd and A. Ward. (1988).

Ciprofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutics use. Drugs. 35: 373-447.

Hammerman, A., A. Greenberg, and A. M. Yinnon (2003). Drug use evaluation of ciprofloxacin:impact of educational efforts on appropriateness of use. J.Clin Pharmacy & Ther., 22(5): 415-420.

Hyatt, J. M., D. E. Nix and J. J. Schentag (1994). Pharmacokinetics and Pharmacodynamics activities of ciprofloxacin against strains of streptococcus Pneumonia, Staphylococcus aureus, and Pseudomonas aeruginosa for which MICs are similar. Anti. Microb.Agent Chemother., 38 (12): 2730-7.

Iqbal, Nawaz, T., R. Ilahi, and M. Nawaz (1989). Disposition kinetics of sulphadiazine in normal and diabetic rabbits. J Pak Med Assoc., 39 (2): 50-53.

Lehninger, A. L. (1975). Biochemistry: Diabetes Mellitus 2nd Ed. Worth Publisher New York: 845-849.

Nawaz, M., S Akhtar and A. S. Hashmi (1982). Disposition kinetics and urinary excretion of sulphadimidine in normal and alloxan diabetic dogs. Acta. Pharmacol. ET. Toxicol., 51: 63-68.

Neu, H. C. (1987). Ciprofloxacin: a major advance in quinolone chemotherapy. Am J Med., 82 (Suppl. 4A): 1.

Qamar, S., N. Irfan, M.Ahmad, M Jamshaid and N.A. Muzaffer (1997). The bioavailability and pharmacokinetics of mefnamic acid in alloxan-diabetic rabbits. Tokai J. Exp Clin Med., 22 (4): 163-166.

Raina, R., S Prawez, D. J Dimitrove, N. K. Pankaj and P. K. Verma (2008). Disposition kinetics and urinary excretion of ciprofloxacin in goats following single intravenous administration. J.Vet. Sci., 9 (3), 241-245.
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Publication:Pakistan Journal of Science
Article Type:Report
Geographic Code:9PAKI
Date:Sep 30, 2010
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