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A PHARMACOKINETIC-PHARMACODYNAMIC MODEL FOR GENE-REGULATED PROSTATE MAINTENANCE: COMPARING THE EFFECTS OF CASTRATION WITH ANTIANDROGEN EXPOSURE IN THE RAT
Zager, M. G., L. K. Potter, AND H A. Barton. A PHARMACOKINETIC-PHARMACODYNAMIC MODEL FOR GENE-REGULATED PROSTATE MAINTENANCE: COMPARING THE EFFECTS OF CASTRATION WITH ANTIANDROGEN EXPOSURE IN THE RAT. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Antiandrogens affect prostate maintenance in two ways. Androgen antagonists, such as the fungicide vinclozolin, act as competitive ligands for the androgen receptor (AR). Enzyme inhibitors, such as the therapeutic drug Finasteride, inhibit the enzyme 5 -reductase (5 R) from metabolizing testosterone (T) to the more potent dihydrotestosterone (DHT). Each mode of action results in decreased DHT levels and hence decreased prostate size. Castration leads to nearly total removal of T and DHT from the body, resulting in acute, significant prostate regression. A model describing the pharmacokinetics (PK) of T, DHT, luteinizing hormone (LH), and antiandrogens was linked to a pharmacodynamic (PD) model describing the androgen-controlled gene regulation of the prostate in the adult male rat. The resulting PK-PD model is able to simulate the prostatic effects of castration and antiandrogen exposure. The model describes the metabolism of T to DHT by 5 R with feedback loops for the positive regulation of T synthesis by LH and negative regulation of LH by T and DHT. The gene-regulated processes involved in prostate maintenance, including cell proliferation, apoptosis, fluid production, and 5 R activity, are each controlled in the model by the occupancy of a single gene by androgen-AR dimerized complexes. The model accurately captures the dynamics of the prostate after castration vs. daily doses of Finasteride, compared with experimental data. Daily dosing of Finasteride results in significantly decreased levels of DHT and raised levels of T due to the feedback loop. The result is approximately 60 percent prostate regression after 21 days compared to over 90 percent regression due to castration. This modeling effort provides a framework for extension from the adult to the more sensitive pubertal developmental period by including growth and changes in hormone synthesis and metabolism. (Funded by EPA/UNC Training Agreement CT827206. This abstract does not reflect EPA policy.)