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Download this complete Project material titled; Effect Of Green Tea (Camellia Sinensis) On The Pharmacokinetic Profile Of Cephalexin In Healthy Human Volunteers with abstract, chapters 1-5, references, and questionnaire. Preview Abstract or chapter one below

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ABSTRACT

Tea is a herb commonly consumed globally. Herbs are often taken concurrently with conventional medicines which results in increased potential of drug-herb interactions, and this may have important clinical significance based on an increasing number of reports of such interactions. This research work, determines the effects of green tea (Camellia sinensis) on the pharmacokinetic profile of cephalexin in healthy human volunteers. Quality control studies were conducted on a sample of cephalexin (500 mg) capsule to establish identity, weight uniformity, disintegration time, dissolution, and as well as assay using the methods of BP 1993 and BP 2013.A UV spectrophotometric method for determining cephalexin in plasma using water as a solvent at pH 4 was developed and validated based on international conference on harmonization (ICH) guidelines. For the in vivo study, six apparently healthy human volunteers were used throughout the study. The study involved four phases with one week washout period between the phases; phase I (administration of cephalexin alone), phase II (concurrent administration of cephalexin with aqueous extract of green tea), phase III (administration of cephalexin one hour after ingestion of aqueous extract of green tea) and phase IV (administration of cephalexin one hour before ingestion of aqueous extract of green tea). Blood samples (2 mL) were collected in a heparinized sample bottles from each of the six volunteers at 0, 0.5, 1, 2, 3, 4 and 6 hours. Plasma proteins were precipitated using 20 μL of 40 % perchloric acid, followed by centrifugation and buffering of the supernatant with 1 ml phosphate buffer pH 4, and subsequently volumes were adjusted to 5 ml with distilled water. Samples were analysed for cephalexin content using the developed UV method and pharmacokinetic parameters generated for each of these phases. The results of quality control studies revealed that the cephalexin 500 mg capsule passed the test. It was found to contain the labeled active
pharmaceutical ingredient and results for uniformity of weight, dissolution, and desintegration time were within the accepted range of 92.5 – 110 % , ˂ 7.5 %, ≥ 90 % and ˂ 15 minutes respectively. The calibration curve was found to be linear within the range of 5 – 150 μg/mL as its coefficient of determination (r2 = 0.9994) close to unity with a regression equation of y = 0.0045 – 0.0178. UV spectral analysis revealed 261 nm as the wavelength of maximum absorption of cephalexin in water at pH 4. Percentage recovery was found to be 84.5 – 85.5 % which is outside the accepted range of 98 – 102 %. The mean plasma concentration of cephalexin in phase I were found to be 13.50, 69.00, 58.60, 48.00, 42.60 and 12.40 (μg/mL) at time 0.5, 1, 2, 3, 4 and 6 (hours) respectively. The Cmax (μg/mL) for phases I, II, III and IV were found to be 69.00, 79.95, 68.00 and 87.07 (μg/mL) respectively at time 1 hour (Tmax) except for phase III with Tmax of 2 hours. Their AUCs were found to be 235172, 302982, 354333 and 244449 μg/L*h respectively. With the exception of Tmax of phase II and IV, Cmax of phase III, and also the clearance (Cl) of phase IV, all other pharmacokinetic parameters of phases II, III and IV determined were found to be significantly different (p ˂ 0.05) from those of phase I (control) . Therefore, it can be concluded that Camellia sinensis (green tea) aqueous extract was found to significantly (p ˂ 0.05) enhance the extent and the rate of absorption, decreased elimination rate of cephalexin as well as increase in its volume of distribution to the peripheral compartments.

 

TABLE OF CONTENTS

Title page……………………………………………………………………………………………………………………i
Declaration…………………………………………………………………………………………………………………ii
Certification……………………………………………………………………………………………………………….iii
Aknowledgement……………………………………………………………………………………………………….iv
Abstract…………………………………………………………………………………………………………………….v
Table of contents……………………………………………………………………………………………………….vii
List of tables……………………………………………………………………………………………………………..xii
List of figures…………………………………………………………………………………………………………..xiii
Abbreviations…………………………………………………………………………………………………………..xiv
Equations………………………………………………………………………………………………………………..xvi
List of Appendices…………………………………………………………………………………………………..xvii
CHAPTER ONE
1.0 INTRODUCTION………………………………………………………………………1
1.1 Pharmacokinetics………………………………………………………………………….1
1.1.1 Absorption ………………………………………………………………………………..2
1.1.2 Distribution………………………………………………………………………………..3
1.1.3 Metabolism………………………………………………………………………………..3
1.1.4 Elimination……………………………………………………………………………….4
1.2 Drug Interaction…………………………………………………………………………..4
1.2.1 Classification of drug interaction…………………………………………………………4
1.2.2 Consequences of drug interaction…………………………………………………………4
1.2.3Mechanism of drug interaction………………………………………………………………………………5
1.3 Herbal Medicines…………………………………………………………………………..7
1.3.1 Green tea…………………………………………………………………………………….8
1.4 Statement of the Research Problem……………………………………………………….8
1.5 Justification of the Research……………………………………………………………….9
1.6 Aim and Objectives………………………………………………………………………….9
1.6.1 Aim…………………………………………………………………………………………9
1.6.2 Objectives………………………………………………………………………………..9
1.7 Research Question/Hypothesis………………………………………………………….10
1.7.1 Null hypothesis…………………………………………………………………………..10
1.7.2 Alternate hypothesis………………………………………………………………………10
CHAPTER TWO
2.0 LITERATURE REVIEW………………………………………………………………11
2.1 Chemistry of Cephalexin………………………………………………………………..11
2.1.1 Pharmacokinetics of cephalexin……………. ……………………………………………..12
2.1.2 Mechanism of action……………………………………………………………………12
2.1.3 Uses and administration………………………………………………………………….13
2.1.4 Adverse effects…………………………………………………………………………..13
2.1.5 Interactions of cephalexin…………………………………………………………………14
2.2 Green Tea Constituents and their Interactions ………………………………………..14
2.2.1 Pharmacodynamic interactions of green tea with cephalosporins………………………..16
2.2.2 Pharmacodynamicinteractions of green tea with other antibiotics……………………….16
2.2.3Mechanism of interaction of green tea……………………………………………………17
2.3 Reported Methods of Cephalexin Analysis………………………………………………17
2.3.1 Spectrophotometry……………………………………………………………………….18
2.3.2 HPLC: The modern method of cephalexin analysis……………………………………….19
CHAPTER THREE
3.0 MATERIALS AND METHODS………………………………………………………22
3.1 Materials…………………………………………………………………………………..22
3.1.1 Drugs…………………………………………………………………………………….22
3.1.2 Glass wares……………………………………………………………………..………..22
3.1.3 Equipment……………………………………………………………………..…………23
3.1.4 Chemical reagents…………………………………………………………………………23
3.2 Methods……………………………………………………………………………………24
3.2.1 Sample collection……………………………………………………………….………..24
3.2.2 Quality control of cephalexin standard powder………………………………………….25
3.2.3 Quality control of cephalexin capsule……………………………………………………26
3.2.4 Analytical method ………………………………………….……………………..…………29
3.2.5 Validation of the developed analytical method:…………………………………………30
3.2.6In-vivo interaction studies of cephalexin and green tea aqueous extract…………………32
3.2.7 Data analysis……………………………………………………………………………..34
CHAPTER FOUR
4.0 RESULT…………………………………………………………………………..……35
4.1 Quality control of Cephalexin Standard Powder………………………………………35
4.1.1 Identification of cephalexin standard powder……………………………………………35
4.2 Quality Control of Cephalexin capsule………………………………………………….36
4.2.1 Physical evaluation of cephalexin capsule sample………………………………………..36
4.2.2 Identification of cephalexin capsule………………………………………………………37
4.2.3 Assay of cephalexin capsule …………………………………………………………….38
4.2.4 Results for uniformity of weight and dissolution……….…………………………………..38
4.2.5 Disintegration time of cephalexin capsule……………………………………………… ..39
4.3 Results of Analytical Method Development……..………………………………………..40
4.3.1 Determination of wavelength of maximum absorption………………………….……….40
4.3.2 Determination of pH of maximum absorption…………………………………………….41
4.3.3 Calibration curve………………………………………………………………………….42
4.4 Validation of the Analytical Method……………………………………………………..43
4.4.1 Precision of the analytical method…………………………………………….……………43
4.4.2Accuracy and percentage recovery studies……………………………………………………………45
4.4.3 LOQ and LOD of the developed method………………………………………..…………..46
4.5 Results of In-vivo studies…………………………..…………………………………………47
CHAPTER FIVE
5.0 DISCUSSION……………………………………………..………………………………….52
5.1 Quality Control of Cephalexin Standard Powder and Capsule……………………………52
5.2 Analytical Method Development……………………………………………………………..53
5.4 In-vivo Studies Results……………………………………….……………………………………..54
CHAPTER SIX
6.0 SUMMARY AND CONCLUSION…….……..………………………………………56
6.1 Summary……………………..…………………………………………………………………56
6.2 Conclusion…………………………………………………………………………………………………………57
6.3 Recommendations……………………………………………………………………………………………..57
REFERENCES……………………………………………………………………………..58
APPENDICES……………………………………………………………………………………………………….

 

 

CHAPTER ONE

1.0 INTRODUCTION
1.1 Pharmacokinetics
The term pharmacokinetics was first introduced by Dost (1953) in his book titled “Der blutspiegel”. Kinetics is that branch of knowledge which involves the change of one or more variables as a function of time. According to Gibaldi and Levy (1976) Pharmacokinetics is concerned with the study and characterization of the time course of drug absorption, distribution, metabolism, excretion and with the relationship of these processes to the intensity and time course of therapeutic and adverse effect of drugs. Wagner(1981) also defined Pharmacokinetics as the study of rate process associated with absorption, distribution, metabolism and excretion of drugs, and according to him 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. Another more recent definition is the one put forward by Hedaya (2007) which defined pharmacokinetics as the study of kinetics of drug absorption, distribution, metabolism and elimination. It is important to study the rate of absorption of drug because faster drug absorption leads to faster onset of drug effect which is critical in treatment of acute condition and in emergency situations. Understanding the extent of drug absorption is also important because not all the total dose administered is the amount that is responsible for producing the drug effect but only the amount of drug absorbed and made available at site 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 (Hedaya, 2007). Each pharmacokinetic process (absorption, distribution, metabolism and excretion) is associated with one or more parameters that are dependent on the drug, drug product and the patient (Hedaya, 2007).Pharmacokinetics is useful in selecting and adjusting drug dosage schedules and monitoring drug levels (therapeutic and toxic concentrations).Pharmacokinetic parameters include area under the curve (AUC), maximum plasma concentration (Cmax), time to attain maximum concentration (Tmax), absorption half-life(tα1/2), absorption rate constant (Kα), elimination half-life (tβ1/2), elimination rate constant (Kβ), Plasma clearance (Cl), volume of distribution (Vd) and lag time ( Tripathi, 2013).
1.1.1 Absorption
This is the first stage, for orally administered drugs. Absorption is the movement of a drug from its site of administration into the central compartment (mostly blood) and the extent to which this occurs (Buxton, 2006). For solid dosage forms, absorption first requires dissolution of the tablet or capsule; this liberates the drug into the systemic circulation where it will be distributed to its sites of action, and clinicians are concerned primarily with bioavailability rather than absorption (Buxton, 2006). Drug absorption provides avenue for drug interactions, either negatively or positively. Negative interaction occurs when absorptionof a drug is greatly reduced by another drug i.e. Co-administration of iron preparation with tetracycline where the absorption of tetracycline is greatly reduced by iron. Positive interaction could occur by increasing the absorption of another drug. For example, anticholinesterases increase absorption of some drugs by increasing gastric emptying time (Katzunget al., 2004).
1.1.2 Distribution
Following absorption or systemic administration into blood stream, a drug distributes into interstitial and intracellular fluids. This process reflects a number of physiological factors and the particular physicochemical properties of individual drug. Cardiac output, regional blood flow, capillary permeability, and tissue volume determine the rate of delivery and potential amount of drug distributed into tissues. Initially, liver, kidney, brain and other well-perfused organs receive most of the drug, whereas delivery to muscle, most viscera, skin and fat is slower. This second distribution phase may require minutes to several hours before the concentration of drug in tissue is in equilibrium with that in blood. It also involves a far larger fraction of body mass than does the initial phase and generally accounts for most of the extravascularly distributed drug. Therefore tissue distribution is determined by partitioning of drug between blood and a particular tissue and the more important determinant of that is the relative binding of drug to plasma proteins and tissue macromolecules (Buxton, 2006).
1.1.3 Metabolism
Metabolism is the transformation of drug by chemical alteration to form metabolites. The metabolites are disposed of either in the urine or bile, this overall process is referred to as metabolism (Katzunget al., 2004). Metabolism of drugs and other xenobiotics into more hydrophilic metabolites is essential for their elimination from the body, as well as for the determination of their biological and pharmacological activity. In general, biotransformation reaction generates more polar, inactive metabolites that are readily excreted from the body. However, in some cases, metabolites with potent biological activity or toxic properties are generated. Drug metabolism or biotransformation reactions are classified as either phase I (Functionalization reactions) or phase II biosynthetic (Conjugation) reactions (Buxton, 2006).
The primary site of drug metabolism is liver; others are kidneys, intestines, lungs and plasma (Tripathi, 2013).
1.1.4 Elimination
This is a general term referring to drug removal from the body by any mechanism (Katzunget al., 2004). Drugs are eliminated from the body either unchanged by the process of excretion or converted to metabolites. Excretory organs, the lung excluded, eliminate polar compounds more efficiently than substances with high lipid solubility. Lipid-soluble drugs are not readily eliminated until they are metabolized to more polar compounds. The kidney is the most important organ for excreting drugs and their metabolites. Drug substances excreted in the faeces are principally unabsorbed orally ingested drugs or drug metabolites excreted either in the bile or secreted directly into the intestinal tract and not reabsorbed (Buxton, 2006).
1.2 Drug Interaction
A drug interaction is an interaction between a drug and some other substances, such as another drug or a certain type of food or herb, which prevents the drug from working correctly. An interaction can either increase or decrease the effectiveness and/or the side effects of a drug, or it can create a new side effect not previously seen before (APA, 2002).
1.2.1 Classification of drug interaction
There are various categories of drug interactions which include drug-disease, drug-drug, drug-food, drug-herb and drug-environmental interactions (Linnarson, 1993).
1.2.2 Consequences of drug interactions
Drug Interactions can result in one or more of the following outcomes: reduction in the desired effect of a drug, increase in adverse effects of a drug, unnecessary pain and suffering, increase in
the beneficial effect of a drug, decrease in the adverse effects of a drug and increased cost of treatment (APA, 2002).
Drug interactions may lead to an increase or decrease in the beneficial or the adverse effects of the given drugs(Bogenschutz and Bojrab, 2003; Synder, et al., 2011).When a drug interaction increases the benefit of the administered drugs without increasing side effects, both drugs may be combined to increase the control of the condition that is being treated(Bogenschutz and Bojrab, 2003; Synder, et al., 2011). For example, drugs that reduce blood pressure by different mechanisms may be combined because the blood pressure lowering effect achieved by both drugs may be better than with either drug alone(Bogenschutz and Bojrab, 2003; Synder, et al., 2011).The absorption of some drugs is increased by food. Therefore, these drugs are taken with food in order to increase their concentration in the body and, ultimately, theireffect(Bogenschutz and Bojrab, 2003; Synder, et al., 2011). Conversely, when a drug’s absorption is reduced by food, the drug is taken on anempty stomach (Bogenschutz and Bojrab, 2003).
Drug interactions that are of greatest concern are those that reduce the desired effects or increase the adverse effects of the drugs(Bogenschutz and Bojrab, 2003; Synder, et al., 2011).
1.2.3Mechanism of drug interaction
Knowledge of the mechanism by which a given drug interaction occurs is often useful in practice, as the mechanism could influence both the time course and methods of evading the interaction (Linnarson, 1993).There are several mechanisms by which drugs interact withother drugs, food, and other substances (Baxter and Stockley, 2008).
An interaction can result when there is an alteration (whether increase or decrease) in one of the followings: absorption of a drug into the body, distribution of the drug within the body, metabolism and/or elimination of the drug from the body.
Most of the important drug interactions result from a change in the absorption, metabolism, or elimination of a drug. ((Baxter and Stockley, 2008).
1.2.3.1Change in absorption
Most drugs are absorbed into the blood and then travelled to their sites of action. It is the most common drug interaction and is said to occur in the intestine. The mechanism of drug interaction due to absorption can be summarized as follows:
(a) an alteration in blood flow to the intestine;
(b) change in drug metabolism (breakdown) by the intestine;
(c) increased or decreased intestinal motility (movement);
(d) alterations in stomach acidity, and
(e) change in the bacteria that reside in the intestine.
Drug absorption can also be affected if the drug’s ability to dissolve (solubility) is changed by another drug or if a substance (for example, food) binds to the drug and prevents its absorption (i.e. chelation) (Kushuba and Bertino, 2007).
1.2.3.2Change in drug distribution
Change in drug interaction is said to occur when the concentration of a drug at the site of action is changed without necessarily altering its circulating concentration(Bogenschutz and Bojrab, 2003; Synder, et al., 2011).This becomes more alarming for drugs with intracellular
or central nervous system targets(Bogenschutz and Bojrab, 2003; Synder, et al., 2011). Examples of drugs that cause significant changes in the cell membrane transport of other drugs are:
a. verapamil which inhibits efflux transporters (e.g. P-glycoprotein) there by increasing the concentrations of substrates such as digoxin and cyclosporin.
b. probenecid by inhibiting anion transporters (e.g. OAT-1) causes increase in the concentrations of substrates such as methotrexate and penicillin.
Drug interactions involving transport are less well understood than drug interactions involving metabolism (Synder, et al., 2011).
1.3 Herbal Medicines
Herbs and fruits have been used by man from prehistoric times. They are used for various reasons ranging from nutritional, therapeutic, to social reasons (include use as aphrodisiacs) (Odimgbe, 1998). Herbal medicines are becoming popular worldwide, despite their mechanisms of action being generally unknown, the lack of evidence of efficacy, and inadequate toxicological data. An estimated one third of adults in developed nations and more than 80% of the population in many developing countries use herbal medicines in the hope of promoting health and to manage common maladies such as colds, inflammation, heart disease, diabetes and central nervous system diseases (Zhou et al., 2007).
There are more than 11,000 species of herbal plants that are in use medicinally to date, and of these about 500 species are commonly used in Asian and other countries. These herbs are often taken concurrently with conventional drugs, raising the potential of drug-herb interactions, which may have important clinical significance based on an increasing number of clinical reports of such interactions (Zhou et al., 2007).
1.3.1Green tea
Tea is one of the herbs commonly consumed globally. It is the processed leaves of Camellia sinensis plant. Camellia sinensisis the source of black, green, oolong and white teas, it is an evergreen shrub indigenous to Southeast Asia. A difference in the method of processing of harvested leaves and buds of the plant is responsible for the varieties. White tea is made from very young tea leaves or buds; green tea is made from mature unfermented leaves; Oolong tea from partially fermented leaves; and black tea from fully fermented leaves (Reygaert,2014).
Studies have suggested that green tea may contribute to a reduction in the risk of cardiovascular diseases and some forms of cancer as well as promotion of oral health and other physiological functions such as anti-hypertensive effect, body weight control, ultraviolet protection, bone mineral density increase and neuro-protection power (Cabrera et al., 2006; Jazani et al., 2007).
1.4 Statement of the Research Problem
Tea is a herb that is commonly consumed (Costa et al., 2002) and it has been estimated that, about 25% of all prescription drug users take tea concomitantly with conventional medications (Gurley et al., 2008). A good number of in-vitro studies have reported that green tea or its constituents enhance the antibacterial action of cephalosporins (Passat, 2012) and other groups of antibiotics (Lee et al., 2005; Jazaniet al., 2007). However, there are other reports of green tea inhibiting the antibacterial action of cephalosporins (Passat, 2012) and other groups of antibiotics (Esimoneet al., 2013; Ihekweremeet al., 2015).
1.5 Justification of the Research
There appears to be conflicting claims on the effect of green tea on the antibacterial activity of some cephalosporins and other antibiotics.However, there have been no reports on the pharmacokinetics interaction between green tea and cephalexin. Thus, the need to study the pharmacokinetic profile of cephalexin when co-administered with green tea, in order to explain the pharmacokinetic basis for some of the reported pharmacodynamic interactions.
1.6 Aim and Objectives
1.6.1 Aim
The aim of this study is to determine the effect of green tea on the pharmacokinetic profile of cephalexin in healthy human volunteers.
1.6.2 Objectives
The objectives of this study are to;
a. carry out quality control assessment of both reference standard and cephalexin 500 mg capsule to be used in the study.
b. develop and validate a UV-Spectrophotometric method for the analysis of cephalexin in human plasma.
c. determine the pharmacokinetic profile of cephalexin when administered alone and when co-administered with green tea extract in healthy human volunteers.
1.7Hypothesis
1.7.1 Null hypothesis
Green tea extract has no significant effect on the pharmacokinetics of cephalexin in healthy human volunteers.
1.7.2 Alternate hypothesis
Green tea extract has significant effect on the pharmacokinetics of cephalexin in healthy human volunteers.

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