Pharmacokinetics/Pharmacodynamics (PK/PD) of Oral Diethylstilbestrol (DES) in Recurrent Prostate Cancer Patients and of Oral Dissolving Film (ODF)-DES in Rats
| dc.contributor.advisor | Chow, Diana Shu-Lian | |
| dc.contributor.committeeMember | Liang, Dong | |
| dc.contributor.committeeMember | Hussain, Tahir | |
| dc.contributor.committeeMember | Alkadhi, Karim A. | |
| dc.contributor.committeeMember | Tu, Shi-Ming | |
| dc.creator | Ako, Roland | |
| dc.date.accessioned | 2012-04-19T14:08:47Z | |
| dc.date.accessioned | 2012-04-19T14:08:50Z | |
| dc.date.available | 2012-04-19T14:08:47Z | |
| dc.date.available | 2012-04-19T14:08:50Z | |
| dc.date.created | August 2011 | |
| dc.date.issued | 2011-08 | |
| dc.date.updated | 2012-04-19T14:08:50Z | |
| dc.description.abstract | Prostate cancer is the most diagnosed non-skin cancer and the second leading cause of cancer related death in men in the United States. According to the National Cancer Institute (NCI), an estimated 217,730 men were diagnosed with prostate cancer in 2010 and 32,050 died from the disease. For metastatic disease patients, response to treatment is short-lived (2 to 3 years), and the disease progresses to an androgen-independent form which is irresponsive to hormonal treatment, and usually results in death in less than 18 months (Saitoh et al., 1984). Estrogens like diethylstilbestrol (DES) have been used for the treatment of advanced prostate cancer (PCa) for more than half a century. The use of DES to treat advanced PCa is associated with excess cardiovascular side effects like deep vein thrombosis, pulmonary embolism, heart attack and stroke. DES was replaced by luteinizing hormone releasing hormone (LHRH) agonists which have a safer side effects profile. There has been renewed interest in DES because it is effective in treating hormone-independent advanced PCa, and LHRH agonists are not. We are interested in optimizing the dosing regimens of oral DES therapy by using patient DES plasma concentrations as a guide. This objective was achieved by developing a robust and efficient LC/MS/MS assay for the quantification of DES in human and rat plasma, and using the assay to quantify DES concentrations in the plasma of 19 patients enrolled in a clinical phase II trial. We are also interested in investigating other routes of administration and/or formulations of DES that will bypass the first-pass liver metabolism and potentially increase bioavailability and decrease DES toxicity. The side effects of DES have been associated with its metabolism in the liver which is believed to alter the body’s coagulation cascade. This aim was achieve by studying the transdermal delivery of a solution of DES in propylene glycol through mouse skin, and establishing the merits of the transbuccal delivery of DES using an oral dissolving film (ODF)-DES in rats. We quantified DES concentrations in plasma of 19 patients on oral DES capsules for recurrent PCa and correlated DES plasma levels with response by PSA decline. We suggest a DES plasma level of 2 ± 1 ng/ml as a therapeutic target. We also demonstrated the potential merits of ODF-DES in rats; ODF-DES increases significantly the bioavailability (AUC of ODF: 179.07 ng/ml*h, AUC of oral suspension: 65 ng/ml*h) of DES by a factor of 2.7 with minimal effects on the clotting proteins evaluated. The significance of the observation is that a less DES dose from ODF-DES can achieve comparable concentration as a higher dose from oral formulation, which may potential decrease DES side effects. | |
| dc.description.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/10657/251 | |
| dc.language.iso | eng | |
| dc.rights | The author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Diethylstilbestrol | |
| dc.subject | LC-MS/MS | |
| dc.subject | Fibrinogen | |
| dc.subject | Antithrombin | |
| dc.subject | Pharmacokinetics | |
| dc.subject | Prostate cancer | |
| dc.subject | Oral Dissolving Film(ODF) | |
| dc.subject.lcsh | Pharmacokinetics | |
| dc.title | Pharmacokinetics/Pharmacodynamics (PK/PD) of Oral Diethylstilbestrol (DES) in Recurrent Prostate Cancer Patients and of Oral Dissolving Film (ODF)-DES in Rats | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| thesis.degree.college | College of Pharmacy | |
| thesis.degree.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| thesis.degree.discipline | Pharmaceutics | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.major | Pharmacokinetics | |
| thesis.degree.name | Doctor of Philosophy |