title: A multiscale, mechanism-driven, dynamic model for the effects of 5α-reductase inhibition on prostate maintenance.
abstract: A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound binding properties, dosing regimens, and target validation.
authors.affiliation: Dynamics and Metabolism, Worldwide Research and Development, Pfizer, Inc, San Diego, California, United States of America. michael.zager@pfizer.com
authors.forename: Michael G
authors.initials: MG
authors.lastname: Zager
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Barton
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002138:Calibration; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018120:Finasteride / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D013739:Testosterone / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D018120:Finasteride; D042944:Cholestenone 5 alpha-Reductase