Effects of Environmental Exposure on the Pharmacokinetics of Ciprofloxacin Tablet in Healthy Human Volunteers
CHAPTER ONE
Specific objectives of the study
- To carry out quality control assessment of the non-exposed (reference) and exposed ciprofloxacin tablet using Pharmacopoeia standards (B.P 2002, 2009).
- To adopt and validate a UV spectrophotometric method for analysis of ciprofloxacin in biological samples (saliva).
- To generate the pharmacokinetic profiles of the non-exposed (reference) with the exposed ciprofloxacin tablet samples from saliva concentrations.
- To compare the pharmacokinetic profiles of the non-exposed (reference) with the exposed ciprofloxacin tablet samples from saliva concentrations.
CHAPTER TWO
LITERATURE REVIEW
Introduction
The term pharmacokinetic was first introduced by F.H. Dost in 1953 in his book Der blutspiegel (Wagner, 1981). Although previously some of the subject matter were published before the word was coined, the term pharmacokinetics was later defined in a number of ways (Wagner, 1981). Literally, the word means the application of kinetics to pharmakon, the Greek word for drugs and poisons. Kinetics is that branch of knowledge which involves the change of one or more variables as a function of time. The purpose of pharmacokinetics is to study the time course of drug and metabolites concentrations or amount in biological fluids, tissues and excreta, and also of pharmacological response, and to construct suitable models to interpret such data. In pharmacokinetics, the data are analyzed using a mathematical representation of a part or the whole of an organism. Broadly then, the purpose of pharmacokinetics is to reduce data to a number of meaningful parameter values, and to use the reduced data to predict either the results of future experiments or the results of a host of studies which would be too costly and time-consuming to complete (Wagner, 1981). Gibaldi and Levy in 1976 defined pharmacokinetics as follows: “Pharmacokinetics is concerned with the study and characterization of the time course of drug absorption, distribution, metabolism and excretion, and with the relationship of these processes to the intensity and time course of therapeutic and adverse effects of drugs. It involves the application of mathematical and biochemical techniques in a physiologic and pharmacologic context (Wagner, 1981).
It is important to study pharmacokinetic processes because the onset, intensity and duration of drug action depend on them. Faster drug absorption leads to faster onset of drug effect which is critical in treatment of acute condition and in emergency situations. Also, not all the dose of drug administered through extravascular routes reaches systemic circulation. Extent of drug absorption determines the amount of drug in the body and its intensity of action. Studying the drug distribution is necessary because the drug has to be taken to the site of action to elicit its effect. Also studying the rate of drug elimination is important so as to know the frequency of drug administration. Drugs that are eliminated faster are administered more frequently so as to maintain an effective drug concentrations at all times during multiple drug administrations. Studying the organs responsible for drug elimination is also critical because patients with organ dysfunctions require dosage adjustments. As a result, it is critical to know the factors that can affect the pharmacokinetic process of each drug (Hedaya, 2007).
Order of Kinetics
Linear pharmacokinetics
Linear Pharmacokinetics is also known as dose-independent or concentration independent pharmacokinetics. Parameters such as half-life, total body clearance, and volume of distribution are constant and do not depend on the drug concentration or the amount of the drug in the body. It is also called first order processes. Therefore, when there is a change in drug dose it results in a proportionate change in the drug concentration-time profile in the body (Dhillon and Gill, 2006; Hedaya, 2007).
Non-linear pharmacokinetics
Non-linear Pharmacokinetics is also known as capacity-limited, dose dependent or saturation pharmacokinetics (Shargel et al., 2010). This is because the pharmacokinetics parameters such as half-life, total body clearance and possibly volume of distribution are dependent on the drug concentration and the drug amount in the body. Here, at least one of the pharmacokinetics processes that affect the concentration-time profile inside the body is saturable and hence does not follow first order kinetics (Dhillon and Gill, 2006). When there is a change in drug dose it results in disproportionate increase or decrease in the concentration time-profile in the body (Hedaya, 2007). Thus, in non-linear pharmacokinetics, the AUC and the amount of drug excreted not proportional to the dose. Also, the elimination half-life may increase at high doses and the ratio of metabolites formed changes with increased dose. It is also known as zero order kinetics (Shargel et al., 2010).
CHAPTER THREE
MATERIALS AND METHODS
Materials
Pharmaceutical grade ciprofloxacin standard powder made by May and Baker (M&B-UK) was used for the method development and validation. Ciprofloxacin tablet (500 mg) made in India, registered with NAFDAC and with long shelf life (expiry date of 01/05/2018) was purchased directly from Evans Pharmaceutical company.
The following solvents of analytical grade were used: 0.1M HCI (M&B–UK), 0.1M NaOH, Ethanol, Methanol, Chloroform, Acetone (Sigma-Germany), and Distilled water. Also, Phosphate buffer (pH 4) was used.
The apparatus used in this study includes: UV spectrophotometer (Thermo-Scientific Helios Zeta UV-Vis, ser. no; UV2-164917) with1cm path length, Analytical weighing balance (DENVER-ISTRUMENT (Apx-200), Friabilator, Disintegration apparatus (Erweka), and Dissolution apparatus (USP apparatus-basket method).
Methods
Study area
The study was conducted in Gombe State. Gombe State is located in the North Eastern part of Nigeria. It shares borders with all the 5 states of the North eastern region. Gombe State was created in 1996 and has an estimated population of 2.6 million in 2010 with a population density of 128 persons per sq. km (Abdulkadir et al., 2013). It is divided into 3 senatorial zones: Gombe North, Gombe Central and Gombe South. The state has eleven (11) Local Government Areas (LGAs). Gombe North comprises of 5 LGAs: Gombe, Kwami, Dukku, Funakaye, and Nafada. Gombe Central zone comprises of 2 LGAs: Akko and Yamaltu-Deba. While Gombe South comprises of 4 LGAs: Billiri, Kaltungo, Balanga, and Shongom. The state experiences two seasons: wet and dry seasons. The rainfall intensity is high between July and August. The dry season is between November and April with the coldest month experienced between the month of December and January.
CHAPTER FOUR
RESULTS
In vivo Pharmacokinetic Results
Mean saliva concentration-time profiles of ciprofloxacin tablet samples A, B, C and D
The mean saliva concentration-time profiles of ciprofloxacin after administration of 500 mg dose to each volunteer for the non-exposed sample (A) and all the three exposed samples (B, C, and D) are presented (Appendix XVII) and their respective saliva concentration-time curves shown in figure 4.1
The non-exposed ciprofloxacin tablet (Sample A) reached a peak saliva concentration of 10.12 ± 3.94 μg/ml at 6 hr as illustrated in figure 4.1 and Appendix XVII. Sample B is the exposed ciprofloxacin tablet to Gombe north which reached its peak saliva concentration of 11.59 ± 2.75 μg/ml at 6 hr. While samples C and D (ciprofloxacin tablets exposed to Gombe central and Gombe south respectively) reached their peak saliva concentrations of 8.83 ± 1.84 μg/ml for sample C and 7.10 ± 2.46 μg/ml for sample D at 7 hr each. Figure 4.1 shows super-imposed concentration-time curves of all the ciprofloxacin samples. The result shows that the saliva concentration of non-exposed ciprofloxacin tablet (Sample A) was higher than for the two exposed samples C and D but is lower than the exposed sample B. It can also be seen from the graph that the time to reach peak salivary concentrations for sample C and D were the same but shifted to the right and higher than for the non-exposed sample A.
CHAPTER FIVE
DISCUSSION
The ciprofloxacin tablet sample was collected directly from a pharmaceutical company. Its package label information was examined and found to have a NAFDAC registration number, manufacturing date, batch number, expiry date and the name of its country of origin. This indicates that the drug product was legally imported and registered with the Nigerian drug regulatory body: National Agency for Food and Drug Administration and control (NAFDAC).
Summary
The quality control of ciprofloxacin tablet sample was carried out using 2002, 2009 B.P and USP 2005 standards. The parameters determined were identification, assay, disintegration, dissolution and friability tests. The results indicated that both the exposed and the non-exposed drug samples showed positive to identification and passed both friability and disintegration tests. While the dissolution and the assay parameters of the exposed sample D was less than the accepted limit of ≥ 70% and 95-105% respectively indicating less quality compared to others. The method that was applied was adopted and validated by U.V/VIS spectrophotometry. The parameters for both method adopted (i.e solubility and λmax) were determined and validated. The validation parameters used were: precision (within day and between day) measured as percentage relative standard deviation (% RSD), linearity, and percentage extraction recovery.
In the in vivo studies, the following pharmacokinetic parameters were generated: Cmax, Tmax, AUC0-∞, lag time, t1/2α, t1/2β, Kα, Kβ, Vd, Cl. They were compared at P ≤ 0.05 between the non exposed (sample A) and the exposed samples B, C, and D respectively. When sample A (non-exposed) was compared with each of the samples B, C, and D, there was no significant difference except between sample A and D which showed a significant change in elimination half life and elimination rate constant. This may be due to effect of the exposure in the zone. Elimination half life and elimination rate constant are parameters that determine how drugs are removed from the body.
High elimination rate constant means the exposed drug will have shorter half life. This may give a sub-therapeutic drug level and loss of antibacterial activity.
Conclusion
It can be concluded from this study that exposure to environmental factors in Gombe South significantly affected the elimination half life and elimination rate constant of ciprofloxacin tablet and which could have a significant clinical implications.
Recommendation
It is recommended that Pharmacokinetic studies of this kind should be extended to other antibiotics in Gombe state.
Contributions to knowledge
The study was able to adopt, validate and applied an analytical method for in vivo quality assessment of ciprofloxacin. The study established an in vitro quality control parameters of ciprofloxacin tablet exposed to environmental factors in three zones of Gombe state. The study also generated and compared the pharmacokinetic profiles of ciprofloxacin between the non-exposed and the exposed samples and found a significant change in two of the parameters of the exposed sample in zone D.
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