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Title of Thesis

Shahnaz Gauhar
Institute/University/Department Details
Department of Pharmaceutics/ University of Karachi
Number of Pages
Keywords (Extracted from title, table of contents and abstract of thesis)
pefloxacin,nsaid, paracetamol, fluoroquinolone, pefloxacin mesylate

The study of pharmacokinetics gives substantial evidence that the method of manufacture and the proper formulation of the drug can markedly affect the bioavailability of the drug. It is important for Pakistani manufacturers that they should study the pharmacokinetics of their products for the assurance of bioavailability, safety and efficacy of their product.

The search for better and safer drugs has been one of the foremost aims of man. Remedies obtained from various sources have been used in the ancient time for the treatment of diseases. In the early days these remedies were administered to the patient in the crude form, which was not only inconvenient to the patients, but also the doses administered were inappropriate.

In the earlier days the effectiveness of two drug products containing the same active ingredients and manufactured by different manufacturers was compared by measuring the biological response in-patient, which was extremely difficult to quantify. Now-a-days, using blood levels and/or urinary excretion rates of the unchanged drug and/or its metabolites have proved' to be convenient, cheaper, faster and reliable method for measuring the drug response in patient. The prime reason for this is the discovery of specific and sensitive analytical techniques of HPLC. With HPLC method of analysis pharmacists, scientists and researchers are able to trace the course of the drug i.e., absorption, distribution, metabolism and elimination (ADME) in the body accurately.

In the present study the first aim was to modify the method developed by A1-Obaidy et al., (1995) and validate a simple High-Performance Liquid Chromatographic method (HPLC) for the determination of a fluoroquinolone i.e., Pefloxacin in plasma. The test involves plasma protein precipitation with ethyl acetate under neutral condition, followed by drying at room temperature in open air and dissolving in mobile phase before chromatographic analysis. The drug was eluted from shim-pack CLC - ODS at room temperature with a mobile phase consisting of 13% acetonitrile in 0.025 M phosphoric acid solution (pH=2.9) at a flow rate of 1 ml/min. The test sample was monitored on an UV detector. The %CVs of the retention times and of the peak areas of pefloxacin from the six consecutive injections of the system suitability solution injected were 0.566% and 0.989%, respectively. The results show that the peak area responses are linear within the concentration range of the analysis. The correlation coefficient, r2, was 0.9965. In this study Limit of detection (LOD) and limit of quantitation (LOQ) were evaluated based on pefloxacin mesylate compound in which the peak responses were the lowest concentration of analyte in a sample with acceptable precision and accuracy under the stated experimental conditions. These LOD and LOQ were estimated at 0.0625µg/ml and 0.125 µg /ml, respectively. The method was shown to be linear, quantitative and reproducible. This method can be used successfully in pharmacokinetic studies in human.

Pefloxacin mesylate tablets 400mg which was originally a research product of Rhone-Poulenc-Rorer Pharmaceutical, is now being manufactured by more than 10 local manufacturers in Pakistan. The pharmacokinetics including its bioavailability and bioequivalence tests are not performed even on a single brand marketed in Pakistan.

Nearly all-Pharmaceutical products, which are manufactured and marketed in Pakistan, are the research products of developed countries. All test and trials, which are necessary for the registration of the drugs in Pakistan, were conducted in the country where it was originally developed. In Pakistan, Pharmaceutical manufacturer are simply engaged in manufacturing of several brands of a single generic drug on the basis of original research of the parent company. Where as it is a fact that the drug products, which are originated in, home countries are according to their own population feasibility and condition. Where as the people of Pakistan are quite different with respect to their physiological systemic absorption of a drug from the gastrointestinal tract or any other extravascular site which dependent on the physicochemical properties of the drug, dosage form of the drug, diet, and climate. Therefore it will be risk to apply the pharmacokinetics studies of the parent company on our population without any authentic clinical research.

In present study 8 different brands of pefloxacin mesylate tablets 400mg, which were manufactured by multinational and local pharmaceutical companies, were collected from the local market. Physico-chemical tests such as weight variation; disintegration, dissolution and pharmaceutical assay were performed on these brands. All brands passed the physico-chemical parameters.

Antimicrobial susceptibility test of pefloxacin mesylate in comparison of three different fluoroquinolones against standard E.coli and S. aureus were also studied. The in-vitro antibacterial activities of pefloxacin, ciprofloxacin, norfloxacin and ofloxacin, were assessed by dilution method, by determination of minimum inhibitory concentrations (MICs) against E.coli (A TCC-8739) and S. aureus (A TCC -6538). The comparative result shows that the 4- quinolones were all highly active against E.coli. Pefloxacin (MICs = 0.2508 µg/ml) have same efficacy, as that of norfloxacin and ofloxacin but ciprofloxacin (MICs = 0.060 µg/m) was the most active. Similarly the result shows that the activity of pefloxacin (MICs =0.2508 µg /ml) was same to that of ciprofloxacin and ofloxacin but greater than that of norfloxacin (MICs =2.0 µg/ml) against S. aureus. The result is similar to that of the result reported by king and Phillips, (1986); Malik et al., (2002) Nordmaun and Jarlier (1990). The study was conducted to investigate some of the phannacokinetics differences and individual variation of oral pefloxacin tablet 400mg alone (as control) and in the presences of oral paracetamol tablet 500mg (as treatment) in healthy local population. On the basis of physico-chemical studies, a brand was selected out of 9 brands for bioavailability and pharmacokinetics studies. Cross-over, two-phase study was used in which 10 healthy volunteers were selected. Each volunteer received pefloxacin mesylate tablet 400mg alone (control) in 1st phase and pefloxacin mesylate tablet 400mg + paracetamol tablet 500mg concomitantly (treatment) in 2nd phase. Blood samples were collected from volunteers at 0, 0.5, 1, 1.5, 2, 3, 5, 7, 8, 24, and 32 hours. Plasma was separated and the concentration of drug was determined using HPLC technique. These concentration/time-profiles were then used for calculating the pharmacokinetics parameters.

The investigation shows that the value of AUC0-ˆž (Mean % SEM) in control was 67.355±3.174 µg.h/ml, where as in treatment it appeared as 61.242 ±3.868 µg.h/ml along with relative bioavailability (Mean ± SEM= 91.395 ±4.864). The Mean maximum plasma concentrations (Mean ±SEM) in control and treatment condition were 4.679 ± 0.248 µg /ml and 4.6595 ± 0.266 µg /ml respectively. The Mean Tmax for plasma concentrations was 1.819 ± 0.1743 hr and 1.605 ± 0.1 134 hr respectively. The Mean absorption half- lives (Mean ± SEM) in both states control and treatment were 0.407 ± 0.049hr and 0.33 ± 0.028hr respectively. The biological half-lives (Mean ± SEM) in the two phases of studies were found to be 7.953 ± 0.33hr in control and 7.7257 ± 0.355hr in treatment. The Mean volume of distribution (Mean ± SEM) was 74.868 ±3.7971itre and 76.464 ± 4.04351itre respectively. The Mean distribution coefficient (Mean ±SEM) in control and treatment condition was 0.9954 ±0.06461itre/kg and 1.0266 ±0.07491itre/kg respectively. Total clearance (Mean ±SEM) in two phases of studies was found to be 6.5799 ±0.3651itre/hr in control and 6.9869 ±0.50161it/hr in treatment. The values of Mean Residence Time (MRT) in control and treatment states (Mean ±SEM) were found to be 11.934 ± 0.518hr and 11.625 ± 0.516hr respectively.

Pharmacokinetics results of pefloxacin tablets 400mg alone and in combination of paracetamol tablets 500mg were also evaluated by statistical bioequivalence test of ANOV A two ways. Results of the present study clearly suggest that the bioavailability of pefloxacin tablet in healthy Pakistani volunteers is very closely similar to the results reported by other workers (Malik et al., 2002; Montay et al., 1984; Barre et al., 1984; Gonzalez and Henwood, 1989; Lepeleire, 1988). The data of present study may be used for evaluating the pharmacokinetic character of the drug in local population.

The result shows that the concomitant administration of paracetamol with pefloxacin has no significant effect on the bioavailability and pharmacokinetics of pefloxacin, however, minor differences noticed might relate with inter-individual variation in human volunteers.

FDA requires Cmax, Tmax, and AUC as a necessary bioavailability and bioequivalence parameter to be monitored for the registration of a new formulation. In Pakistan health regulating agencies also follow the same pattern for some of the categories of drugs but not for all.

Finally on the basis of these studies it is suggested that a strict monitoring by the health regulating agencies is required and there must be a proper protocol for conducting physico-chemical and pharmacokinetics test for every product to be marketed in Pakistan. Especially because of racial difference, every new product, which is to be launched in Pakistan, must be subjected to these pharmacokinetics tests.

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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents
560.17 KB
2 1 Introduction 1
2161.98 KB
  1.1 Objectives Of Study 6
  1.2 Pharmacokinetics Study Of Drug 7
  1.3 Polypharmacy As Regard To Drug-Drug Interaction Or Related Problems 24
  1.4 Introduction Of Pefloxacin Mesylate 35
  1.5 Analgesics, Antipyretics And Anti-Inflammatory Drug 55
  1.6 Drug-Drug Interaction And /Or Related Problems 61
  1.7 Assay Of Drugs In Dosage Form 62
3 2 Literature Survey 69-122
1414.11 KB
4 3 Experimental 123
710.93 KB
  3.1 Pharmaceutical Quality 123
  3.2 Pharmacokinetics Evaluation Of Pefloxacin 139
  3.3 Statistical Evaluation Of The Data 158
5 4 Results 161
5790.64 KB
  4.1 In-Vitro Evaluation Of Pefloxacin Mesylate Tables 161
  4.2 Antimicrobial Susceptibility Test Of Pefloxacin Mesylate & Its Comparison With 3 Different Quinolones 191
  4.3 Validation Of Analytical Procedure Of Pefloxacin 204
  4.4 Pharamcokinetic Study Of Pefloxacin (Alone) And In The Presence Of Paracetamol 218
6 5 Discussion & Conclusion 252
662.94 KB
  5.1 Discussion 252
  5.2 Conclusion 278
7 6 References 280
711.74 KB
  6.1 Appendix 322