Clozapine Toxicity: Role Of Pharmacogenetic Variation In CYP Enzymes And Bioactivation Mechanisms In Patient Neutrophils
Funder
National Health and Medical Research Council
Funding Amount
$336,000.00
Summary
The treatment of mental disorders such as schizophrenia involves the administration of potent drug combinations to patients. Some individuals, however, do not respond to commonly-used antipsychotic drugs and their condition only improves with a unique drug called clozapine. The major problem with clozapine is its toxicity toward blood cells, heart and other organs. All people who receive clozapine must be monitored closely, especially in the first 3-4 months after starting therapy. Several new d ....The treatment of mental disorders such as schizophrenia involves the administration of potent drug combinations to patients. Some individuals, however, do not respond to commonly-used antipsychotic drugs and their condition only improves with a unique drug called clozapine. The major problem with clozapine is its toxicity toward blood cells, heart and other organs. All people who receive clozapine must be monitored closely, especially in the first 3-4 months after starting therapy. Several new drugs have been suggested to be safer versions of clozapine but these are all ineffective. Clozapine is the only agent that is effective in people who do not respond to the other drugs used to treat schizophrenia. Thus, clozapine toxicity, which necessitates discontinuation of the drug, is a devastating outcome because there is no alternative treatment that is available. Another significant problem with clozapine is that its rate of removal from the body is slowed down by many other drugs that are used concurrently. The problems with clozapine occur in some but not all individuals. This suggests that the patient's genetic makeup and their exposure to drugs and environmental agents determine the incidence of toxicity. The present project looks at how clozapine is removed from the body and how it is converted into a toxic product that damages cells. These processes will be examined, with emphasis on differences between individual patients, and strategies to protect cells from damage from the toxic derivative will be tested. Corresponding studies will be done in patients who are receiving clozapine as treatment for psychoses. We will be able to compare experimental and clinical findings in order to identify those patients who appear to be at risk. This will be possible before the toxic effects occur and will help us to identify subjects in whom the drug should only be used with great care. We may also devise strategies that will minimise the incidence of toxicity.Read moreRead less
Repression Of Hepatic Drug Metabolism By Solid Tumours
Funder
National Health and Medical Research Council
Funding Amount
$504,000.00
Summary
The treatment of advanced cancer patients with drugs is difficult due to many confounding factors. The variability between patients in clearance rate has a significant impact on the success of chemotherapy. This is especially relevant to chemotherapeutic agents which have a narrow therapeutic range. Anti-tumour action will be lost if the drug is cleared too rapidly from the body, while high doses will lead to toxic side effects. A better understanding of the source of this variability will lead ....The treatment of advanced cancer patients with drugs is difficult due to many confounding factors. The variability between patients in clearance rate has a significant impact on the success of chemotherapy. This is especially relevant to chemotherapeutic agents which have a narrow therapeutic range. Anti-tumour action will be lost if the drug is cleared too rapidly from the body, while high doses will lead to toxic side effects. A better understanding of the source of this variability will lead to improvements in the manner in which chemotherapy is administered and would represent a welcome advance for cancer patients. The rate of breakdown of drugs in the body is largely determined by the levels of enzymes called cytochrome P450s (CYPs) in the liver. In humans CYP3A4 is responsible for the disposal of more than half of all drugs including several important chemotherapeutic agents. Clinical studies have found that the presence of an inflammatory response to tumours in tissues outside the liver reduces hepatic CYP3A4 activity. Factors released by immune as well as malignant cells within the tumour circulate via the bloodstream to the liver where they alter expression of many genes including CYPs. The study of the regulation of human genes is inherently difficult. It is nearly impossible to gain access to many body tissues in either healthy or sick individuals to examine co-ordinated gene function (or dysregulation). For this reason we made a transgenic mouse model of human CYP3A4 regulation which enables the human situation to be studied. In this project we will identify the tumour-derived factors which switch off the CYP3A4 transgene and analyse the signalling pathways within liver cells which mediate the response. A knowledge of this mechanism will permit the rational design of therapeutic strategies aimed at making chemotherapy safer and more effective. The availability of convenient animal models enables testing prior to clinical application.Read moreRead less