Carbamazepine is a drug which is now widely used for the treatment of both generalised epilepsy (tonic-clonic seizures) and partial epilepsy (with simple or complex symptomatology). This study was undertaken in an attempt to assess the role of the metabolites of carbamazepine, viz. 10, 11-epoxy-carbamazepine and 10, 11-dihydro-10,11-dihydroxy-carbamazepine, with regard to their therapeutic efficacy and the occurrence of side effects of the parent drug. It was also designed to seek a possible explanation as to why certain patients with optimal levels of carbamazepine in plasma fail to respond to therapy. A total of 23 epileptic patients (11 females and 12 males) suffering from either generalised (tonic-clonic) seizures or partial complex seizures took part in the study. The patients were divided into two groups according to their seizure frequency: Responders - those patients who had no seizures in the month prior to entry into the study (12 patients). Non-Responders - those patients who had a minimum of one seizure a week in the month prior to entry into the study (11 patients). Carbamazepine and its metabolites were monitored between 8 a.m. and 6 p.m. by taking blood samples at two hourly intervals. Cerebrospinal fluid (CSF) was also obtained from seven patients in the non-responder group. The drug and its metabolites were assayed simultaneously by the thin-layer chromatographic (TLC) method of Hundt and Clark (1975). Six of the 23 epileptic patients complained of side effects: nausea and headaches were the most frequently mentioned complaint. Statistical analysis showed, however, that there was no significant difference in the peak levels of carbamazepine and metabolites in patients both with or without side effects. Therefore, it was not possible to define a threshold level of the drug above which side effects were likely to occur. Also, no definite conclusion could be reached as to whether the metabolites play a role in the manifestation of side effects. The area under the curve (AUC) is a measure of the overall plasma concentration of carbamazepine and metabolites (present between 8 a.m. and 6 p.m.) in the individual patients of the two groups. There was no significant difference in the AUC of carbamazepine between responders and non-responders. However, the AUC of the dihydroxy and epoxy metabolites was significantly higher in the non-responders (P<-0.002 and P < 0.02 respectively). Moreover, in the CSF samples of the non-responders, the mean (±SD) ratio of the dihydroxy metabolite to the parent drug was as high as 1.17 (±0,36). The results show a clear association between high levels of metabolites and poor response to carbamazepine therapy. Furthermore, it would seem that either both metabolites are inactive or that if the epoxy metabolite is active as in the rat (Frigerio and Morselli 1975), any likely therapeutic effect is counter-acted by the relatively large concentration of inactive dihydroxy metabolite (Schmutz et al 1979). Moreover, it may follow that non-response to carbamazepine - despite optimal levels of the drug in plasma - may be due to competition by inactive dihydroxy metabolite for the site (s) of action of the parent drug in the brain. Research strategies which might be used to test this hypothesis have been proposed.

Tse Kai Kong. / Thesis submitted in: August 1998. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 116-122). / Abstract also in Chinese. / ABSTRACT --- p.ii / 摘要 --- p.v / ACKNOWLEDGEMENTS --- p.viii / CONTENTS --- p.ix / LIST OF FIGURES --- p.xiii / LIST OF TABLES --- p.xvii / ABBREVIATIONS --- p.xix / Chapter CHAPTER ONE --- Introduction --- p.1 / Chapter 1 --- Introduction --- p.2 / Chapter 1.1 --- Definition and Prevalence of Epilepsy --- p.2 / Chapter 1.2 --- Neurophysiology and Pathophysiology of Epilepsy --- p.3 / Chapter 1.3 --- Drugs Currently Used in the Treatment of Epilepsy --- p.5 / Chapter 1.4 --- Triazolines Aminoalkylpyridines as a New Class of Potential Antiepileptic Drugs --- p.9 / Chapter 1.5 --- Chemical Synthesis of Aminoalkylpyridines --- p.14 / Chapter 1.6 --- Metabolism of Aminoalkylpyridines --- p.15 / Chapter 1.7 --- Anticonvulsant Activities of Aminoalkylpyridines --- p.16 / Chapter 1.8 --- Aim and Scope of the Present Study --- p.18 / Chapter CHAPTER TWO --- Experimental --- p.19 / Chapter 2.1 --- MATERIALS --- p.20 / Chapter 2.2 --- PREFORMULATION STUDIES ON AMINOALKYLPYRIDINES --- p.22 / Chapter 2.2.1 --- Determination of Partition Coefficient --- p.22 / Chapter 2.2.2 --- Determination of Aqueous Solubilities --- p.22 / Chapter 2.2.3 --- Determination of Thermal Properties --- p.23 / Chapter 2.3 --- DEVELOPMENT OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC ASSAY FORp-C1 AMINOALKYLPYRIDINES --- p.24 / Chapter 2.3.1 --- HPLC Apparatus and Conditions --- p.24 / Chapter 2.3.2 --- Animal Treatments and Biological Fluid Collection --- p.24 / Chapter 2.3.3 --- Solid Phase Extraction --- p.25 / Chapter 2.3.4 --- Construction of Calibration Curves for p-Cl AAP in Rat Blood --- p.25 / Chapter 2.3.5 --- Construction of Calibration Curves for p-Cl AAP in Rat Urine --- p.26 / Chapter 2.3.6 --- Accuracy and Precision in the Quantitation of p-C1 AAP in Biological Fluids --- p.26 / Chapter 2.4 --- PRELIMINARY PHARMACOKINETICS OF p-C1 AAP FOLLOWING INTRAVENOUS ADMINISTRATION --- p.27 / Chapter 2.4.1 --- Cannulae Preparation --- p.27 / Chapter 2.4.2 --- Dosage --- p.27 / Chapter 2.4.3 --- Animal Surgery and Sample Collection --- p.28 / Chapter 2.4.4 --- Pharmacokinetic Calculations --- p.29 / Chapter 2.5 --- URINARY METABOLIC STUDIES OF p-C1 AAP --- p.30 / Chapter 2.5.1 --- Animal Treatment and Urine Collection --- p.30 / Chapter 2.5.2 --- Deconjugation Assay --- p.30 / Chapter 2.5.3 --- Non-deconjugated Urine Sample Treatment --- p.31 / Chapter 2.5.4 --- Separation of Metabolites by HPLC --- p.31 / Chapter 2.5.5 --- Identification of Metabolites by LC/MS --- p.31 / Chapter 2.5.6 --- Quantitative Analysis --- p.32 / Chapter 2.5.7 --- Preparation of the authentic β-amino alcohol --- p.34 / Chapter 2.6 --- STATISTICAL ANALYSIS --- p.34 / Chapter CHAPTER THREE --- Results and Discussion --- p.35 / Chapter 3.1 --- PREFORMULATION STUDIES ON AMINOALKYLPYRIDINES --- p.36 / Chapter 3.1.1 --- PARTITION COEFFICIENT (K°W) --- p.36 / Chapter 3.1.2 --- AQUEOUS SOLUBILITY --- p.37 / Chapter 3.1.3 --- THERMAL ANALYSIS --- p.41 / Chapter 3.2 --- DEVELOPMENT OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC ASSAY FOR p-C1 AMINOALKYLPYRIDINES --- p.49 / Chapter 3.2.1 --- SOLID PHASE EXTRACTION --- p.49 / Chapter 3.2.2 --- CONSTRUCTION OF CALIBRATION CURVES FOR p-C1 AAP IN THE RAT BLOOD --- p.49 / Chapter 3.2.3 --- CONSTRUCTION OF CALIBRATION CURVES FOR p-C1 AAP IN THE RAT URINE --- p.52 / Chapter 3.2.4 --- ACCURACY AND PRECISION IN THE QUANTITATION OF p-Cl IN THE BIOLOGICAL FLUIDS --- p.54 / Chapter 3.3 --- PRELIMINARY PHARMACOKINETICS OF p-C1 AAP FOLLOWING INTRAVENOUS ADMINISTRATION --- p.57 / Chapter 3.4 --- URINARY METABOLIC STUDIES OF p-C1AAP --- p.61 / Chapter 3.4.1 --- QUALITATIVE STUDIES : IDENTIFICATION OF METABOLITES --- p.61 / Chapter 3.4.2 --- QUANTITATIVE STUDIES --- p.94 / Chapter CHAPTER FOUR --- Conclusion --- p.111 / REFERENCES --- p.115 / APPENDIX Published Papers --- p.121

The pharmacokinetics of phenytoin is complicated by the nonlinearity of the dose-concentration relationship which is a consequence of capacity-limited metabolism. Individualized therapy with phenytoin is therefore optimally required. As no data are available on the population pharmacokinetics of phenytoin in the Western Cape, this study was undertaken to address this issue. This study was conducted prospectively primarily to: (1) investigate the influence of various patient variables on the population pharmacokinetic parameters of phenytoin, (2) assess whether the parallel Michaelis-Menten and first-order elimination model provides a better fit to the data than the Michaelis-Menten model, (3) determine population pharmacokinetic parameter estimates of phenytoin representative of the patient population, and (4) validate and compare the clinical applicability of the parameter estimates and the models. The study population comprised 332 black and coloured, adult, male and female epileptic patients residing in the Western Cape, South Africa. All patients were on phenytoin monotherapy for the management of their epilepsy and no drugs known to interfere with phenytoin pharmacokinetics were taken concurrently. Clinical pharmacokinetic dosing services were initiated at 9 clinics from which patients were selected for this study. The service entailed a patient interview, a chart review, drug analysis and provision of either a written or verbal consultation report. The data were analyzed using NONMEM (nonlinear mixed-effects modelling), a computer programme designed for population pharmacokinetic analysis that allows pooling of data from many individuals. The Michaelis-Menten and the parallel Michaelis-Menten and first-order elimination models were fitted to 853 steady-state dose: serum concentration pairs.