Novel strategies for bioanalysis of hydrophobic antipsychotic drugs and hydrophilic oligonucleotide macromolecules
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Schizophrenia is a severe psychiatric disorder affecting approximately 1.5% of the world’s population. It has long been known that chronic exposure to certain antipsychotics, such as haloperidol, often results in cholinergic imbalances in the striatum and consequently abnormalities in motor function. Given that cognition is now recognized as a key factor that influences long term functional outcome in schizophrenia, it is important to determine if there is a correlation between antipsychotic plasma or brain tissue levels and cognitive function. Since antipsychotic drugs are very active, they are usually administered at low daily dosages. They are extensively metabolized in the body. At steady state, these doses result in plasma levels in the low ng/ml range. In order to carry out pharmacology and toxicology studies, highly sensitive, selective and accurate bioanalytical methods are necessary to determine antipsychotic drugs in biological samples. Most of the antipsychotics are hydrophobic chemicals. It is a challenge to extract them from biological samples, especially from brain tissue. Chapter 1 is the introduction and describes the layout of the dissertation. Chapter 2 reviews the literature for analytical methods for determination of antipsychotic drugs in biological samples. A HPLC-UV method to simultaneously quantitate five antipsychotic drugs including the active metabolite 9-hydroxyrisperidone in rat plasma is included in Chapter 3. LC-MS/MS methods for the simultaneous determination of olanzapine, risperidone, 9-hydroxyrisperidone, clozapine, haloperidol and ziprasidone in rat plasma and brain tissue are described in Chapters 4 and 5. In addition, LC-MS/MS methods developed and validated for the determination of highly hydrophobic antipsychotic drugs (chlorpromazine and ziprasidone) in plasma and brain tissue are presented in Chapters 6 and 7. Phosphorothiate oligonucleotides (PS-ODNs) as therapeutical antisense oligonucleotides are attracting more and more attention. PS-ODNs pose unique analytical challenges. First, PS-ODNs are very hydrophilic macromolecules and highly bound to the biological matrix. It is a challenge to extract them from biological samples. Secondly, it is a challenge to develop analytical methods that enable the baseline separation and quantitation of an intact oligonucleotide, as well as putative metabolites which may differ by one or two nucleotides. A capillary gel electrophoresis method for the determination of a 24-mer oligonucleotide and its chain-shortened metabolites is described in Chapter 8. Sample preparation was performed using a combined phenol/chloroform liquid-liquid extraction, strong anion-exchange column solid-phase extraction and ion-pair HLB solid-phase extraction method.