EFFECTS OF ENVIRONMENTAL EXPOSURE ON THE PHARMACOKINETICS OF CIPROFLOXACIN TABLET IN HEALTHY HUMAN VOLUNTEERS

ABSTRACT

Ciprofloxacin is a fluoroquinolone antibiotic that is commonly prescribed empirically in Nigeria due to its broad spectrum of activity. However, the drug product is illegally handled by drug hawkers that allow the drug to be exposed to some environmental forces which may affect the drug quality and its pharmacokinetic profiles. This study is aimed at assessing pharmacokinetic profiles of exposed samples of ciprofloxacin marketed by hawkers in the three senatorial areas of Gombe State. Sample A represents non-exposed and control while samples B, C and D represent exposure to different environmental conditions in Gombe state for three months. The in vitro quality control of the drug sample was carried out using 2002 and 2009 B.P standards. The parameters determined were identification, assay, disintegration, dissolution and friability test. The method used was adopted and validated by U.V spectrophotometry and a wavelength (λmax) of 271 nm was measured which served as our working wavelength. The validation parameters used were: Precision (within day and between days), percentage extraction recovery and linearity. The linearity of the calibration curve was determined. In the pharmacokinetics studies, six apparently healthy volunteers were enrolled and were administered with 500 mg of ciprofloxacin each with non-exposed and the exposed samples of the ciprofloxacin and saliva samples were collected before and after administration with wash out period of one week intervals between studies. Pharmacokinetic parameters generated were: Cmax, Tmax, AUC0-∞, lag time, t1/2α, t1/2β, Kα, Kβ, Vd, Cl and were compared at P ≤ 0.05 between the sample A and samples B, C, and D respectively. The results indicated that all the samples showed positive to identification test. Friability and disintegration values were within the acceptable limits ( ≤ 1% and ≤ 30 min respectively). The dissolution and assay parameters of the exposed sample D were 66% and 82.9% which were less than the accepted limits of ≥ 70% and 95-105% respectively indicating low quality compared to others. The within day and between day precision were 1.1 and 1.5 % RSD respectively and both were within the acceptable limit of ≤ 2%. The percentage extraction recovery was 98.8% which was within the acceptable range of 95-105%. The calibration curve that was constructed was found to be linear within 1-6 μg/ml with a correlation coefficient of 0.998. When sample A was compared with each of sample B, C, and D, there was no significant difference except between sample A and D which showed a significant (p ≤ 0.05) change in elimination half life (t1/2β), 3.03 h for A and 1.63 h for D; and elimination rate constant (Kβ), 0.28 h-1 for A, and 0.638 h-1 for D. Elimination half life and elimination rate constant are parameters that determine how drugs are removed from the body. Shorter half life shown for sample D means the exposed drug will be easily removed from the body. This may give a sub-therapeutic drug level and loss of antibacterial activity. It can be concluded that the environmental conditions of the senatorial area where ciprofloxacin tablet sample D was exposed affected its assay, dissolution, elimination half life and elimination rate constant profiles thereby affecting its quality and pharmacokinetics.

CHAPTER ONE

INTRODUCTION

1.1 Background

The safety and efficacy of drug products can be guaranteed when their quality is reliable and reproducible from batch to batch. In order to maintain quality, drug manufacturers are expected to test their products during and after manufacturing and at various intervals during the shelf life of the product. The quality of medicines is an integral part of access in light of ensuring that the pharmaceutical products are fit for their intended use, comply with the requirement of the marketing authorization and do not expose consumers to risks (Jackson et al., 2011). A drug product is the finished dosage form (e.g tablet, capsule, injectable) that contains the active pharmaceutical ingredients (API) which in most cases is in association with other inert ingredients also called excipients. (Shargel et al., 2010).

For a product to be of good quality it has to conform to standard requirements as presented in official (national and international) monographs. The monograph contains laid down procedures for the production of specific items and they also contain details on expected quality of such items. For instance, tablets of the same batch should have the following physico-chemical properties: uniform weight, maximum weight variation not to exceed ±5%, uniform and consistent active ingredient, withstand handling stresses but not too hard for disintegration in the gut and release not less than 70% of the active ingredient into dissolution medium within 45 min (Yabo, 1996; Ogar et al., 2015). In practice even when all batches of tablet product conform to these standards, they might not be kept in a good storage condition from the point of manufacture to the point of dispensing to patients. During transit between the two points, drugs are exposed to different environmental conditions. Drug products (e.g tablets) when exposed to environmental forces like light, heat, humidity and stress, their physicochemical properties change (Bajaj et al., 2012). Physicochemical properties determine stability of the drug, its solubility, membrane permeability, and drug affinity to different tissue components (Hedaya, 2007). These changes may ultimately affect the pharmacokinetic profile of the drug product (Yabo, 1996). This is particularly critical with antibiotics whose bactericidal activity is concentration-dependent like ciprofloxacin (Jacobs, 2001).

When pharmaceutical dosage forms are administered, the active ingredient must reach its site of action before the pharmacological effect of the drug is exerted. If the drug is not introduced directly into the intravascular system, then it must be absorbed. This process of absorption is then followed by distribution through the blood plasma and different body fluids, to various tissues and organs of the body, including the site of drug action. The drug is finally distributed to organs that eliminate them through the process of metabolism and excretion which also determine its fate and duration of pharmacological activity (Ogunbona et al., 2014). 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 is called pharmacokinetics (Gibaldi and Levy, 1976).

Pharmacokinetic processes involve the transfer of drug across biologic membranes through various mechanisms such as: passive diffusion, active transport, pore transport, facilitated diffusion and transport by vesicles. Therefore, each pharmacokinetic process may be associated with one or more parameters that are dependent on the drug, drug product and the patient.

Ciprofloxacin is a fluoroquinolone which act by inhibiting bacterial DNA synthesis. It also exhibits a rapid onset of action, and lacks cross-reactivity with penicillin, cephalosporins and the aminoglycosides (Uduma et al., 2011). Two mechanisms have been proposed for its action. The first is through the inhibition of bacterial topoisomerase II (DNA gyrase) and the second is by inhibiting topoisomerase IV (Katzung et al., 2009). Ciprofloxacin displays in vitro activity against most gram-negative and many gram positive pathogenic bacteria, many of which are resistant to a wide range of antibiotics and this is of considerable potential clinical significance (Vance-Bryan et al., 1990). Various side effects have been observed due to therapy with ciprofloxacin such as effects on the central nervous system and the gastro-intestinal tract as well as photosensitivity reactions of the skin. (Tiefenbacher et al., 1994). Absorption of ciprofloxacin after oral administration is rapid with absolute bioavailability of approximately 70%. Ciprofloxacin has shown good penetration and accumulation in tissues with a wide distribution throughout the body. Four metabolites of ciprofloxacin have been identified in the body fluid as desethylene-ciprofloxacin, sulpho-ciprofloxacin, oxo-ciprofloxacin and formayl ciprofloxacin. The terminal disposition half-life is about 3 to 4 hr. Glomerular filtration and tubular secretion account for approximately 66% of the total serum clearance. (Khan et al., 2009).

1.2 Statement of Research Problem

In Nigeria, there are several brands of ciprofloxacin tablet available in the market and due to its brought spectrum of activity, it is prescribed empirically by physicians for the treatment of infectious diseases (Adegbolagun et al., 2007; Ngwuluka et al., 2009). Massive importation of the drug into the country that already has a chaotic drug distribution system has led to the drug being handled by non-professionals (Ogar et al., 2015). As such, the drug is not properly stored and is exposed to all kind of environmental forces like sunlight, heat, humidity and microbial contamination (Ehikwe et al., 2015). Exposure to environmental factors may lead to deterioration of the Active Pharmaceutical Ingredient and the physicochemical properties of the dosage form (Bajaj et al., 2012). These changes may ultimately affect the pharmacokinetic profile of the drug product (Yabo, 1996). Ciprofloxacin has a concentration-dependent pattern of bacterial killing and hence its efficacy will be affected which could further lead to a wide spread development of drug resistance. It could even lead to the formation of toxic principles (Bajaj et al., 2012).

Currently there are fewer studies on the effects of environmental factors on ciprofloxacin tablet pharmacokinetics in Nigeria.

1.3 Justification

Drug distribution network in some West African countries including Nigeria consists of chaotic open markets which act as major sources for procurement which includes: medicine stores, pharmacy outlets, private and public hospitals, wholesalers/retailers and local pharmaceutical manufacturers, agents or representatives of foreign suppliers (Ogar et al., 2015). The result of this chaotic drug distribution makes drug monitoring very difficult. In addition, it gives room to drug hawking in buses, kiosks, by illiterate vendors whose aims are solely profit oriented. The medicines are left under conditions that may facilitate their deterioration (Ehikwe et al., 2015; Ogar et al., 2015). In Gombe state, drug hawking is a common practice. The state is located in tropical region which is characterized by high temperature, adequate sunlight with sometimes high relative humidity and the climatic conditions in the three senatorial zones of the state differ slightly. Exposure of ciprofloxacin tablet to these environmental forces may change its quality, efficacy, safety and ultimately clinical outcomes. This study was to investigate the effects of environmental exposure on the pharmacokinetic profiles of ciprofloxacin tablet. Information obtained from this study can be applied by all stakeholders in the pharmaceutical industry particularly the drug manufacturers, health workers, drug regulatory agencies and other policy makers in Nigeria.

1.4 Aim of the Study

The aim of this study was to determine the effect of environmental exposure on the pharmacokinetics of ciprofloxacin tablet in healthy human volunteers.

1.5 Specific objectives of the study

I. To carry out quality control assessment of the non-exposed (reference) and exposed ciprofloxacin tablet using Pharmacopoeia standards (B.P 2002, 2009).

II. To adopt and validate a UV spectrophotometric method for analysis of ciprofloxacin in biological samples (saliva).

III. To generate the pharmacokinetic profiles of the non-exposed (reference) with the exposed ciprofloxacin tablet samples from saliva concentrations.

IV. To compare the pharmacokinetic profiles of the non-exposed (reference) with the exposed ciprofloxacin tablet samples from saliva concentrations

1.6 Research Hypothesis

Environmental exposure will significantly affect the pharmacokinetic profiles of ciprofloxacin tablet.