THE EFFECTS OF CHLOROQUINE, PARACETAMOL AND PROMETHAZINE ON THE PHARMACOKINETICS OF CHLORPROPAMIDE IN HUMAN VOLUNTEERS

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ABSTRACT

The effect of chloroquine, paracetamol and Promethazine on the pharmacokinetic profile of chlorpropamide was investigated in human subjects.

The batches of chlorpropamide, chloroquine, paracetamol and Promethazine used were subjected to quality control studies using official methods. The drugs complied with the B.P (1993) requirements stated in their monographs.

A high performance liquid chromatography (HPLC) method was developed for the analysis of plasma chlorpropamide concentration. Pharmacokinetic parameters of chlorpropamide were derived with Winnonlin standard non-compartment software programme.

About 16%, 14% and 15% decrease in the mean maximum concentration (C_max) of chlorpropamide was observed following oral

administration of chlorpropamide with chloroquine, paracetamol and Promethazine respectively.

About 44%, 11% and 30% decrease in the area under curve (AUC) of chlorpropamide was observed following concurrent administration of chlorpropamide with chloroquine, paracetamol and Promethazine respectively. The plasma clearance of chlorpropamide increased by 86% following chlorpropamide interaction with chloroquine.

The absorption half-life (t_½a) of chlorpropamide increased by 4%, 85%

and 69% when concomitantly administered with chloroquine, paracetamol and Promethazine respectively.

The elimination constant (K_el) of chlorpropamide was found to have

increased by 100% and decreased by 31% following concomitant administration of chlorpropamide with chloroquine and paracetamol respectively. The elimination half-life (t_½el) of chlorpropamide was found to

have decreased by 47% and increased by 13% and 29% following concomitant administration to chlorpropamide with chloroquine, paracetamol and Promethazine respectively.

The study implied impaired absorption and elimination of chlorpropamide by chloroquine, paracetamol and Promethazine.

		TABLE OF CONTENTS
								PAGE
TITLE PAGE	-	-	-	-	-	-	-	-	i
DECLARATION	-	-	-	-	-	-	-	-	ii
CERTIFICATION	-	-	-	-	-	-	-	-	iii
DEDICATION	-	-	-	-	-	-	-	-	iv
ACKNOWLEDGEMENT		-	-	-	-	-	-	-	v
PUBLICATIONS	-	-	-	-	-	-	-	-	viii
ABSTRACT -	-	-	-	-	-	-	-	-	ix
TABLE OF CONTENT		-	-	-	-	-	-	-	x
LIST OF FIGURES-`		-	-	-	-	-	-	-	xvi
LIST OF TABLES	-	-	-	-	-	-	-	-	xviii
ABBREVIATIONS	-	-	-	-	-	-	-	-	xxi

CHAPTER 1		INTRODUCTION				-	-	-	-	1
1.1	Pharmacokinetics			-	-	-	-	-	-	1
1.1.1	Blood flow		-	-	-	-	-	-	-	3
1.1.2	Protein Binding			-	-	-	-	-	-	4
1.1.3	Lipid solubility and the degree of ionization							-	-	5
1.1.4	Volume of distribution				-	-	-	-	-	6
1.2	Drug bioavailability and its relationship to chemical
	effectiveness			-	-	-	-	-	-	11
1.2.1	Some factors that influence the bioavailability of a drug									14
1.2.1.1	Dosage form and route of administration							-	-	14
1.2.1.2	Solubility		-	-	-	-	-	-	-	15
1.2.1.3	Hepatic binding to plasma proteins						-	-	-	16
1.2.1.4	Drug bindings to plasma proteins						-	-	-	16
1.2.1.5	Interactions (food-drug or drug-drug interactions) -									17
1.2.2	Bioavailability relationship to clinical effectiveness -									17
1.2.3	Drug level monitoring				-	-	-	-	-	20
1.2.4	Drug – Drug interactions -					-	-	-	-	21
1.2.4.1	Pharmacokinetic interactions					-	-	-	-	22
1.2.4.2	Pharmacodynamic interaction					-	-	-	-	28
1.2.4.3	Undesirable drug interactions					-	-	-	-	31

1.2.4.4	Controlling adverse drug interactions							-	-	37
1.3	Diabetes		-	-	-	-	-	-	-	39
1.4	Malaria		-	-	-	-	-	-	-	48
1.5	Objectives and scope of the study						-	-	-	55
CHAPTER 2 -		LITERATURE REVIEW					-	-	-	60

2.1	Chemistry of Chlorpropamide, chloroquine, paracetamol
	and promethazine -	-	-	-	-	-	60
2.1.1	Chemistry of chlorpropamide		-	-	-	-	60
2.1.2	Chemistry of chloroquine		-	-	-	-	62
2.1.3	Chemistry of paracetamol		-	-	-	-	63
2.1.4	Chemistry of promethazine		-	-	-	-	64
2.2	Pharmacokinetics of chlorpropamide, chloroquine,
	paracetamol and promethazine				-	-	66
2.2.1	Pharmacokinetics of chlorpropamide				-	-	66
2.2.2	Pharmacokinetics of chloroquine			-	-	-	66
2.2.3	Pharmacokinetics of paracetamol			-	-	-	68
2.2.4	Pharmacokinetics of promethazine			-	-	-	69
2.3	Pharmacological actions and mechanism of action of
	chlorpropamide, chloroquine, paracetamol
	and promethazine	-	-	-	-	-	71

2.3.1	Pharmacological action and mechanism of action
	of chlorpropamide				-	-	-	-	-	71
2.3.2	Pharmacological action and mechanism of action of 73
	chloroquine -			-	-	-	-	-	-	73
2.3.3	Pharmacological action and mechanism of action of
	paracetamol			-	-	-	-	-	-	75
2.3.4	Pharmacological action and mechanism of action
	of promethazine			-	-	-	-	-	-	75
2.4	Drug – drug interaction studies						-	-	-	77
2.4.1	Controlling adverse drug interactions -							-	-	83
CHAPTER 3		-	MATERIALS AND METHODS							85
3.1	MATERIALS -			-	-	-	-	-	-	85
3.1.1	Drugs		-	-	-	-	-	-	-	85
3.1.2	Equipment		-	-	-	-	-	-	-	85
3.1.3	Reagents		-	-	-	-	-	-	-	88
3.1.4	Glasswares		-	-	-	-	-	-	-	91
3.2	METHODS		-	-	-	-	-	-	-	94
3.2.1	Identification tests for Chlorpropamide, chloroquine,
	paracetamol and Promethazine tablets							-	-	95
3.2.1.1	Chlorpropamide			-	-	-	-	-	-	95
3.2.1.2	Chloroquine -			-	-	-	-	-	-	95

3.2.1.3	Promethazine		-	-	-	-	-	-	96
3.2.1.4	Paracetamol		-	-	-	-	-	-	97
3.2.2	Chemical assay of Chlorpropamide, chloroquine,
	paracetamol and Promethazine tablets and their
	reference standard powders.				-	-	-	-	98
3.2.2.1	Paracetamol tablets			-	-	-	-	-	98
3.2.2.2	Chlorpropamide tablets			-	-	-	-	-	99
3.2.2.3	Chloroquine tablets			-	-	-	-	-	100
3.2.2.4	Promethazine tablets			-	-	-	-	-	101
3.2.3	Dissolution rate test for Chlorpropamide tablets							-	103
3.2.4	Solvent development and optimization studies							-	104
3.2.5	Extraction recoveries			-	-	-	-	-	106
3.2.6	Preparation of standard solutions					-	-	-	107
3.2.7	The pharmacokinetic studies of Chlorpropamide in
	human subjects		-	-	-	-	-	-	108
3.2.7.1	Subjects	-	-	-	-	-	-	-	108
3.2.7.2	Study design		-	-	-	-	-	-	108
3.2.8	Drug level analysis				-	-	-	-	110
3.2.8.1	Preparation of calibration curve -					-	-	-	110
3.2.8.2	Precisions	-	-	-	-	-	-	-	111
3.2.9	Data analysis		-	-	-	-	-	-	111

CHAPTER 4 – RESULTS			-	-	-	-	-	112
4.1	Identification tests for		Chlorpropamide, chloroquine,
	paracetamol and Promethazine tablets					-	-	112
4.1.1	Chlorpropamide tablets		-	-	-	-	-	112
4.1.2	Chloroquine tablets		-	-	-	-	-	112
4.1.3	Paracetamol tablets		-	-	-	-	-	112
4.1.4	Promethazine tablets		-	-	-	-	-	113
4.2	Chemical assay of Chlorpropamide, chloroquine,
	paracetamol and Promethazine tablets, and their
	reference standard powders			-		-	-	113
4.2.1	Chlorpropamide tablets		-	-	-	-	-	113
4.2.2	Chloroquine tablets		-	-	-	-	-	114
4.2.3	Paracetamol tablets		-	-	-	-	-	114
4.2.4	Promethazine tablets		-	-	-	-	-	114
4.3	Dissolution rate test of Chlorpropamide					-	-	116
4.4	Drug level analysis		-	-	-	-	-	117
4.4.1	Optimization studies		-	-	-	-	-	117
4.4.2	Extraction from biological samples				-	-	-	124
4.4.3	Solvent system	-	-	-	-	-	-	125
4.4.4	Chlorpropamide and chloroquine interaction studies in
	human volunteers group I -			-	-	-	-	130

4.4.5	Chlorpropamide and paracetamol interaction studies in
	Human volunteers – group II		-	-	-	-	136
4.4.6	Chlorpropamide and promethazine interaction studies
	in human volunteers – group III			-	-	-	142
CHAPTER 5 – DISCUSSIONS		-	-	-	-	-	149
5.1	Quality control of Chlorpropamide, chloroquine,
	paracetamol and Promethazine tablets				-	-	149
5.1.1	Chlorpropamide tablets	-	-	-	-	-	149
5.1.2	Chloroquine tablets	-	-	-	-	-	150
5.1.3	Paracetamol tablets	-	-	-	-	-	151
5.1.4	Promethazine tablets	-	-	-	-	-	152
5.2	Plasma Drug Level Analysis		-	-	-	-	152
5.3	Pharmacokinetics of Chlorpropamide when co-administered
	with Chloroquine	-	-	-	-	-	154
5.4	Pharmacokinetics of Chlorpropamide when co-administered
	with Paracetamol - -	-	-	-	-	-	156
5.5	Pharmacokinetics of Chlorpropamide when co-administered
	with Promethazine -	-	-	-	-	-	157

CHAPTER 6 - CONCLUSION AND RECOMMENDATIONS -								158
6.1	Summary -	-	-	-	-	-	-	158

6.2	Conclusions -		-	-	-	-	-	-	160
6.3	Recommendations			-	-	-	-	-	161
	References	-	-	-	-	-	-	-	163
	Appendices	-	-	-	-	-	-	-	180

	LIST OF FIGURES
1.1.4	Concentration Vs time profile for plasma in a
	first order		kinetics		-	-	-	-	-	7
1.2	A plot of concentration Vs time for an orally administered
	drug	--	-	-	-	-	-	-	-	13
1.2.2	Effect of bioavailability on pharmacological effects.									19
4.4.1.1	Effect of Acetonitrile on the resolution of chlorpropamide
	and Tolbutamide using solvent system. Acetonitile-water
	with	Beckman ultraspehe ODS column (USA)							-	120
4.4.1.2	Effect of water on the resolution of chlorpropamide
	and Tolbutamide using solvent system
	Acetonitrile-water with				Beckman ultrasphere
	ODS Column (USA).				-	-	-	-	-	121
4.4.1.3	Effect of pH on the resolution of chlorpropamide
	and	Tolbutamide using solvent system
	Acetonitrile – water with Beckman ultrasphere
	ODS	column (USA).			-	-	-	-	-	122
4.4.3.1	(a)	Chromatogram of chlorpropamide and
	tolbutamide extracted				from blank plasma -				-	126

(b) Chromatogram of chlorpropamide extracted from

blank plasma - - - - - - 126

4.4.3.2	High performance liquid chromatogram of an extract
	of test sample obtained from human subjects 4
	hours following oral administration of chlorpropamide. -							127
4.4.3.3	Calibration curve for chlorpropamide in plasma using HPLC. 128
4.4.4	Semi-log plot of chlorpropamide concentration against
	time, following oral administration of chlorpropamide
	(A) and in	combination with		chloroquine (B) in
	6 human subjects.		-	-	-	-	-	135
4.4.5	Semi-log plot of chlorpropamide concentration against
	time following oral administration of chlorpropamide
	(A) and in	combination with		paracetamol (B)
	in 6 human subjects.		-	-	-	-	-	141
4.4.6	Semi-log plot of chlorpropamide concentration against
	time following oral administration of chlorpropamide
	(A) and in	combination with Promethazine (B) in 6
	human subjects. -		-	-	-	-	-	147

		LIST OF TABLES
4.2.1	Quantitative determination of chlorpropamide
	tablets and standard powder.			-	-	-	-	115
4.2.2	Quantitative determination of chloroquine tablets and
	standard powder.	-	-	-	-	-	-	115
4.2.3	Quantitative determination of paracetamol tablets
	and standard powder -		-	-	-	-	-	115
4.2.4	Quantitative determination of Promethazine tablets
	end standard powder		-	-	-	-	-	116
4.3	Percentage of the active ingredient of
	chlorpropamide released in solution.				--	-	-	116
4.4.1.1 Effect of Acetonitrile on the resolution of chlorpropamide
	and tolbutamide using solvent system aetonitrile – water
	with Beckman ultransphere ODS column (USA)						-	118
4.4.1.2	Effect of water on the resolution of chorpropamide and
	Tolbutamide using solvent system acetonitrile-water with
	Beckman ultraspehe ODS column (USA).					-	-	118
4.4.1.3	Effect of pH on the resolution of chlorpropamide
	and Tolbutamide using solvent system
	Acetonitrile – Water with Beckman ultrasphere
	ODS column (USA)		-	-	-	-	-	119

4.4.1.4	Effect of flowrate on the resolution of chlorpropamide
	and Tolbutamide using solvent system
	Acetonitrile – Water with Beckman ultrasphere
	ODS column (USA)	-	-	-	-	-	119

4.4.1	The mean percentage extraction recoveries of
	chlorpropamide from plasma.						124
4.4.2	Precision of the method of analysis using HPLC method
	for within-day and day-to-day.						129
4.4.3	Mean (+SEM) plasma concentration of chlorpropamide

	in 6 human subjects given chlorpropamide
	(A) with Chloroquine (B).		-	-	-	-	133
4.4.5.1 Mean (+SEM) Pharmacokinetic Parameters of

	chlorpropamide following oral administration of
	chlorpropamide (A) with chloroquine (B) in six volunteers. -134
4.4.5.2 Mean (+ SEM) plasma concentration of chlorpropamide

	in 6 human subjects given chlorpropamide (A) and
	with paracetamol (B) -	-	-	-	-	-	139
4.4.6.1	Mean (+SEM) Pharmacokinetic parameters of

	chlorpropamide following oral administration of
	chlorpropamide (A) with paracetamol (B) in six

	volunteers.	-		-	-	-	-	-	139
4.4.6.2	Mean (+SEM) Plasma concentration of chlorpropamide

	in 6 human subjects given chlorpropamide (A) with
	promethazine (B). -			-	-	-	-	-	145
4.4.6.3	Mean (+SEM) pharmacokinetic parameters of

	chlorpropamide following oral administration of
	chlorpropamide (A) with Promethazine (B) in six
	volunteers.	-	-	-	-	-	-	-	146
4.4.6.4 Mean pharmacokinetic parameters of the three study
	groups compared.		-	-	-	-	-	-	148

LIST OF APPENDICES

1. Plasma concentration of chlorpropamide for individual subject

in various study groups. Group I (Chlorpropamide co-administered

with chloroquine) - - - - - - - 180

2. Plasma concentration of chlorpropamide for individual subject

in various study groups. Group II (chlorpropamide co-administered

with paracetamol). - - - - - - 181

3. Plasma concentration of chlorpropamide for individual subject in various study groups. Group III (chlorpropamide co-administered

with promethazine) - - - - - - 182

4. Pharmacokinetic parameters for individual subjects

in group I (chlorpropamide co-administered with chloroquine) 183

5. Pharmacokinetic parameters for individual subjects

in group II (chlorpropamide co-administered with paracetamol) 184

6. Pharmacokinetic parameters for individual subjects

in group III (chlorpropamide co-administered with promethazine) 185

		ABBREVIATIONS
Kel	-	elimination rate constant
Cp	-	plasma concentration
Clr	-	clearance
Vd	-	volume of distribution
AUC	-	area under curve
HPLC	-	High performance Liquid Chlomatography
IDDM	-	insulin dependent diabetes mellitus
NIDDM	-	Non-insulin dependent diabetes mellitus
uv	-	Ultraviolet
WHO	-	World Health Organization
Cp	-	Plasma Concentration
BDH	-	British Drug House
GPR	-	General Purpose Reagent.
nm	-	nanometer
ml	-	Millitre
g	-	microgramme
CV	-	Coefficient of variation
SEM	-	standard error of the mean
BP	-	British pharmacopoeia
min	-	Minute

0_C	-	degree centigrade (Celsius)
LSD	-	Least square difference
ANOVA	-	Analysis of variance
NSP	-	Non-starch polysacckaride
BNF	-	British National Formulary
MIM	-	Multilateral initiative in malaria
TDR	-	Research and Training in Tropical Diseases

CHAPTER ONE

INTRODUCTION

1.1 Pharmacokinetics

Pharmacokinetics is the study of the time course of drug and metabolite levels in different fluids, tissues, and excreta of the body, and of the mathematical relationships required to develop models to interpret such data (Gibaldi and Perrier, 2004). Neligan (2006) defined Pharmacokinetics as the study of what the body does to a drug.

Pharmacokinetics can also be defined as the study of the time course of drug movement in the body during absorption, distribution, metabolism and elimination (excretion and biotransformation) (Sadee and Beelen, 1980; Coker, 2001). Pharmacokinetic studies can be applied for the safe and effective therapeutic management of a patient. The pharmacokinetic profile of a drug strongly influences its delivery to biological targets, thereby affecting its efficacy and potential side effects (Van de water beemd and Gifford, 2003).

The Pharmacokinetics of a compound are typically understood, analyzed and interpreted in the context of their underlying absorption, distribution, metabolism and excretion (ADME) processes (Gram, 2003). However, there is no unique mathematical model for any of these processes, usually a number of different models with different underlying assumptions, parameterization and applicability are concurrent (Poulin and Theil, 2002). Absorption is the process by which a drug proceeds from the site of administration to the site of measurement within the body (Brodie, 2007).

The routes of drug administration are: oral, intravenous, buccal, sublingual, rectal, intramuscular, transdermal, subcutaneous, inhalational and topical (Neligan, 2006). Of all these routes, the usual way of administration is the oral route (Benet, 1998). The rate of absorption of a drug depends upon its dissolution characteristics, its ability to pass through biological membranes and upon a number of physiological variables (gastrointestinal) motility, presence of food in gastrointestinal tract etc. Apart from physiochemical properties of the drug (ionization constant, lipid-en water solubility, molecular radius, diffusion coefficient) also the pharmaceutical formulation may be of extreme importance in determining rate of absorption (Bozler and Van Rossum, 2002). We have linear and non-linear absorptions. Linear absorption is the type of absorption whereby the free diffusion of a drug through biomembranes is the rate limiting step in absorption. The non-linear absorption is the type of absorption where some other steps become the rate limiting step. For instance, dissolution of drug in the gastrointestinal fluid, non-linear phenomenon in the absorption process will arise (Birkett, 2002). Some drugs require the presence of food in the gastrointestinal tract to be absorbed, others on the contrary are better absorbed when taken in an empty stomach (Health Encyclopedia, 2006). Distribution is the process of reversible transfer of a drug to and from the site of measurement (Birkett, 2002). Some of the factors that determine the distribution of a drug in the body are: blood flow; protein binding; and lipid solubility and the degree of ionization.

1.1.1 Blood flow

When a drug is introduced into the body, it enters the blood which carries it to the site of action.

The tissues with the highest blood flow receive the drug first, before those that have low blood flow.

1.1.2 Protein binding

Most drugs bind to proteins, either albumin or alpha-l-acid glycoprotein (AAG), to a greater or lesser extent (Tillement, 1997). Drugs in their free state travel throughout the body, in and out of tissues and have their biological effect. The highly bound drugs have a longer duration of action and a lower volume of distribution. For a drug that is highly protein bound, loads of it should be administered to get a therapeutic effect, as so much of it is bound to protein. The amount of free drug will be increased when another drug competes with a drug for the binding site on the protein. This is really important for drugs that are highly protein bound. For instance, if a drug is 97% bound to albumin and there is a 3% reduction in binding, then the free drug concentration doubles.

The binding affinity of a drug for plasma proteins and the number of available binding sites, are the two factors that determine the degree of plasma protein binding.

Plasma protein concentration is proportional to the number of binding sites. Drug molecules will equilibrate with tissue compartment if plasma protein concentration decreases. The free drug concentration in the plasma (Cp free) and tissue (C+ free) as well as the drug concentration bound to pharmacological active sites in the tissue will increase by an insignificant amount if the drug's volume of distribution is relatively large.

1.1.3 Lipid solubility and the degree of ionization

Highly ionized drugs cannot cross lipid membranes and unionized drugs can cross freely. Morphine is highly ionized, fentanyl is the opposite. Consequently the latter has a faster onset of action. The degree of ionization depends on the pKa of the drug and the pH of the local environment.

Most drugs are either weak acids or weak bases. Acids are most highly ionized at a high pH (i.e in an alkaline environment). Bases are most highly ionized in an acidic environment (low pH). For a weak acid, the more acidic the environment, the less ionized the drug, and the more easily it crosses lipid membranes. Weak bases have the opposite effect (Neligan, 2006).

1.1.4 Volume of distribution (Vd)

Is the amount of drug in the body divided by the concentration in

the blood (Gillian, 2001).

Volume of distribution can also be defined as the amount of drug in

the body relative to the concentration of drug in the blood (or

plasma) (Rowland and Tozer, 1980).

Vd = D

Where Vd is the apparent volume of distribution, D is the drug dose,

and Cp is the plasma concentration of the drug.

Drugs that are highly lipid soluble, such as digoxin, have a very high

volume of distribution (500 litres). Drugs which are lipid insoluble,

such as neuromuscular blockers, remain in the blood, and have a

low volume of distribution.

Plasma concentration (Cp) is the sum of drug that is bound to plasma protein plus drug that is unbound or free. The free or unbound drug is the pharmacologically active moiety, as it is in equilibrium with the receptor site.

Plasma drug concentration can be used to evaluate the adequacy or potential toxicity of a prescribed dosage regimen.

Pharmacokinetic calculations can be sued to modify dosing regimes

so as to maximize the therapeutic response while minimizing the risk

of toxicity (Mary and Lloyd, 1992).

Steady-state concentration is the drug concentration at which the body is in equilibrium (i.e the rates of drug absorption and elimination are equal). Elimination is the irreversible loss of drug from the site of measurement. A constant fraction of the drug in the body is eliminated per unit time. The rate of elimination is proportional to the amount of drug in the body.

The fraction of the drug in the body eliminated per unit time is determined by the elimination constant (K_el). This is represented by

the slope of the line of the log plasma concentration versus time (Regina, et al, 2006).

Rate of elimination = clearance x concentration in the blood. Elimination rate constant (k_el) is a function of the drugs volume of

distribution and its clearance. It can be calculated by dividing the clearance of the drug by its volume of distribution.

K_el = Clr

Where K_el is the elimination constant, Clr is the clearance, while Vd

is the volume of distribution. The elimination rate constant is utilized to predict how the plasma concentration varies with time, assuming no additional drug is added. For example, if Cp₁ is the initial plasma

concentration and Cp₂ is the plasma concentration after an interval

of decays, Cp₂ can be calculated using the elimination rate constant.

Cp₂ = Cp₁ e-^Kelt

e-^Kelt is the fraction of the initial plasma concentration which is remaining at the end of the time interval.

Most drugs are eliminated by renal excretion and metabolism. The clearance (Clr) of a drug is the volume of plasma from which the drug is completely removed per unit time. Clearance is a proportionality constant which makes the rate of drug elimination equal to the rate of drug administration at steady state (Mary and Lloyd, 1992).

Clearance = elimination constant x volume of distribution

Clr = K_el x Vd

(Neligan, 2006; Regina, et al, 2006).

Increased clearance reduces the AUC (AUC: Area Under Curve) after single drug doses, and leads to a reduced mean steady state concentration during multiple dose therapy.

Decreased drug clearance will increase the AUC during single or multiple drug doses and lead to higher plasma concentration during chronic therapy. Total clearance is equal to the sum of the individual clearances for renal excretion and metabolism.

Total clearance = renal clearance + metabolic clearance

Excretion is the irreversible loss of the chemically unchanged drug.

Drug loss by the kidneys is determined by the next effects of glomerular filtration, tubular secretion and tubular reabsorption. Glomerular filtration is not greatly influenced by other drugs, although displacement from protein binding sites may lead to increased concentration of drug in glomerular fluid and enhanced renal elimination.

The pH of the tubular fluid is a determinant of drug's reabsorption. The clearance of acidic drugs is greater in an alkaline urine, while the clearance of basic drugs is more rapid in acidic urine (Solomon, 2000). Drug metabolism is the conversion of one chemical species to another. Metabolism terminates a drug's effects, as drug metabolites are usually devoid of pharmacological activity.

Metabolism of drugs can lead to the formation of polar (lipid-insoluble) derivatives which can undergo renal excretion. Many commonly used drugs are oxidized in the hepatic endoplasmic reticulum (Smith, 2001). Elimination half-life (t_1/2el) is the time taken

for plasma concentration to reduce by 50%.

The half-life of a drug is dependent upon its volume of distribution and clearance. The relationship is as follows:

K_el = the log of 2 divided bv the t_1/2el = 0.693

t1/2el

Likewise, Clr	=	K_el x Vd
So, Clr	=		0.693 x Vd
				t1/2el
And then, t_1/2el =				0.693 x Vd
And then, t_1/2el =				Clr
				Clr

The half-life of a drug is of importance during maintenance therapy, to estimate the dosing interval. It can be used to predict the time it will take for a patient on a constant dosage regimen to reach a steady state. It can also be used to predict the time it will take for all the drug to be eliminated from the body.

1.2 Drug bioavailability and its relationship to clinical

effectiveness

Bioavailability is the fraction of the administered dose that reaches the systemic circulation (Gibaldi and Perrier, 2004). It can also be said to be the rate and extent to which the active drug ingredient is absorbed at the site of action.

Bioavailability is 100% for intravenous injection but varies for other routes of drug administration. For a drug administered orally, the bioavailability is the area under the curve of a plot of plasma concentration versus time, as shown in the diagram below (Fig. 2).

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