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 (Cmax) 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 (t½a) of chlorpropamide increased by 4%, 85%

 

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

 

The elimination constant (Kel) 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 (t½el) 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

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i

DECLARATION

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ii

CERTIFICATION

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iii

DEDICATION

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iv

ACKNOWLEDGEMENT

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v

PUBLICATIONS

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viii

ABSTRACT  -

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ix

TABLE OF CONTENT

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LIST OF FIGURES-`

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xvi

LIST OF TABLES

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xviii

ABBREVIATIONS

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xxi


 



 

 

 

CHAPTER 1

INTRODUCTION

 

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1

1.1

Pharmacokinetics

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1

1.1.1

Blood flow

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3

1.1.2

Protein Binding

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4

1.1.3

Lipid solubility and the degree of ionization

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5

1.1.4

Volume of distribution

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6

1.2

Drug bioavailability and its relationship to chemical

 

 

effectiveness

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-

-

-

11

1.2.1

Some factors that influence the bioavailability of a drug

14

1.2.1.1

Dosage form and route of administration

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14

1.2.1.2

Solubility

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-

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-

-

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15

1.2.1.3

Hepatic binding to plasma proteins

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-

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16

1.2.1.4

Drug bindings to plasma proteins

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-

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

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20

1.2.4

Drug – Drug interactions -

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21

1.2.4.1

Pharmacokinetic interactions

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22

1.2.4.2

Pharmacodynamic interaction

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28

1.2.4.3

Undesirable drug interactions

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31



1.2.4.4

Controlling adverse drug interactions

 

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37

1.3

Diabetes

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39

1.4

Malaria

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48

1.5

Objectives and scope of the study

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-

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55

CHAPTER 2 -

LITERATURE REVIEW

 

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-

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60


 

 

2.1

Chemistry of Chlorpropamide, chloroquine, paracetamol

 

 

and promethazine -

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-

-

-

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60

2.1.1

Chemistry of chlorpropamide

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-

-

-

60

2.1.2

Chemistry of chloroquine

 

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-

-

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62

2.1.3

Chemistry of paracetamol

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-

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63

2.1.4

Chemistry of promethazine

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-

-

-

64

2.2

Pharmacokinetics of chlorpropamide, chloroquine,

 

 

 

paracetamol and promethazine

 

 

-

-

66

2.2.1

Pharmacokinetics of chlorpropamide

 

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-

66

2.2.2

Pharmacokinetics of chloroquine

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-

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66

2.2.3

Pharmacokinetics of paracetamol

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-

-

68

2.2.4

Pharmacokinetics of promethazine

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-

-

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

-

-

-

-

-

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75

2.4

Drug – drug interaction studies

 

-

-

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77

2.4.1

Controlling adverse drug interactions -

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83

CHAPTER 3

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MATERIALS AND METHODS

 

85

3.1

MATERIALS -

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-

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85

3.1.1

Drugs

 

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85

3.1.2

Equipment

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-

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85

3.1.3

Reagents

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-

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88

3.1.4

Glasswares

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91

3.2

METHODS

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94

3.2.1

Identification tests for Chlorpropamide, chloroquine,

 

 

paracetamol and Promethazine tablets

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95

3.2.1.1

Chlorpropamide

-

-

-

-

-

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95

3.2.1.2

Chloroquine -

-

-

-

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95



3.2.1.3

Promethazine

-

-

-

-

-

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96

3.2.1.4

Paracetamol

-

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-

-

-

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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

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103

3.2.4

Solvent development and optimization studies

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104

3.2.5

Extraction recoveries

-

-

-

-

-

106

3.2.6

Preparation of standard solutions

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-

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107

3.2.7

The pharmacokinetic studies of Chlorpropamide in

 

 

 

human subjects

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108

3.2.7.1

Subjects

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-

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108

3.2.7.2

Study design

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108

3.2.8

Drug level analysis

 

 

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110

3.2.8.1

Preparation of calibration curve -

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-

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110

3.2.8.2

Precisions

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111

3.2.9

Data analysis

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111


 


CHAPTER 4 – RESULTS

 

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-

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112

4.1

Identification tests for

Chlorpropamide, chloroquine,

 

 

paracetamol and Promethazine tablets

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112

4.1.1

Chlorpropamide tablets

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-

-

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112

4.1.2

Chloroquine tablets

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-

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112

4.1.3

Paracetamol tablets

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112

4.1.4

Promethazine tablets

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-

-

-

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113

4.2

Chemical assay of Chlorpropamide, chloroquine,

 

 

 

paracetamol and Promethazine tablets, and their

 

 

 

reference standard powders

-

 

-

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113

4.2.1

Chlorpropamide tablets

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-

-

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113

4.2.2

Chloroquine tablets

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-

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114

4.2.3

Paracetamol tablets

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-

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114

4.2.4

Promethazine tablets

-

-

-

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114

4.3

Dissolution rate test of Chlorpropamide

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116

4.4

Drug level analysis

 

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117

4.4.1

Optimization studies

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-

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117

4.4.2

Extraction from biological samples

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124

4.4.3

Solvent system

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-

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125

4.4.4

Chlorpropamide and chloroquine interaction studies in

 

 

human volunteers group I -

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130



4.4.5

Chlorpropamide and paracetamol interaction studies in

 

 

Human volunteers – group II

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-

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136

4.4.6

Chlorpropamide and promethazine interaction studies

 

 

in human volunteers – group III

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142

CHAPTER 5 – DISCUSSIONS

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-

-

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149

5.1

Quality control of Chlorpropamide, chloroquine,

 

 

 

paracetamol and Promethazine tablets

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-

149

5.1.1

Chlorpropamide tablets

-

-

-

-

-

149

5.1.2

Chloroquine tablets

-

-

-

-

-

150

5.1.3

Paracetamol tablets

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-

-

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151

5.1.4

Promethazine tablets

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-

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152

5.2

Plasma Drug Level Analysis

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152

5.3

Pharmacokinetics of Chlorpropamide when co-administered

 

with Chloroquine

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-

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154

5.4

Pharmacokinetics of Chlorpropamide when co-administered

 

with Paracetamol - -

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-

-

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156

5.5

Pharmacokinetics of Chlorpropamide when co-administered

 

with Promethazine -

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-

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157

 

 

 

 

CHAPTER 6 - CONCLUSION AND RECOMMENDATIONS -

158

6.1

Summary   -

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-

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158


6.2

Conclusions -

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-

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160

6.3

Recommendations

 

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-

-

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161

 

References

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163

 

Appendices

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-

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180


 

 

 

 

 

 

 

 


 

LIST OF FIGURES

 

 

 

 

 

 

1.1.4

Concentration Vs time profile for plasma in a

 

 

 

first order

kinetics

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-

-

-

-

7

1.2

A plot of concentration Vs time for an orally administered

 

drug

--

-

-

-

-

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-

-

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


 


0C

-

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

 

Cp

 

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 (Kel). 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 (kel) 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.

 

Kel                                                                                  =             Clr

Vd

 

Where Kel 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                              =        Kel 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 (t1/2el) 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:

 

Kel = the log of 2 divided bv the t1/2el = 0.693

t1/2el

 

Likewise, Clr

=

Kel x Vd

So, Clr

=

 

0.693 x Vd

 

 

 

 

 

t1/2el

And then, t1/2el =

 

 

0.693 x Vd

 

 

 

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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