BIOLOGICAL MODELS International Science Forum on Computational Toxicology May 21–23, 2007 Research Triangle Park, North Carolina Hugh A. Barton 1, Laura.

Slides:



Advertisements
Similar presentations
Informationsteknologi Institutionen för informationsteknologi | State estimation in endocrine systems with pulsatile hormone secretion Alexander.
Advertisements

Testosterone and 5-Alpha Reductase Inhibitors Stephen Chromi, PharmD PGY-1 Pharmacy Practice Resident St. Joseph’s/Candler Health System.
Dosimetry in Risk Assessment and a bit More Mel Andersen McKim Conference QSAR and Aquatic Toxicology & Risk Assessment June 27-29, 2006.
Mechanisms of Thyroid Toxicity Kevin M. Crofton Neurotoxicology Division National Health and Environmental Effects Laboratory US Environmental Protection.
Chemical pollutants of the food chain. Catherine Viguié CR INRA.
Endocrine Disruptor Screening Program: Ralph L. Cooper Endocrinology Branch Reproductive Toxicology Division NHEERL, U.S. EPA Male and Female Pubertal.
Evaluating Existing in vitro Endocrine Data Jeff Pregenzer, Director of Endocrine Studies, CeeTox.
The Efficacy of Synthetic Steroids to Inhibit Hormonal Receptors Malik D. Lewis Howard University Department of Chemistry
CHAPTER 10 Basic Biopharmaceutics
John C. O’Connor DuPont Haskell Laboratory for Health and Environmental Sciences The 15-Day Intact Adult Male Assay As An Alternative Tier I Screening.
Copyright 2002 Marc Rigas Issues in Exposure Assessment Marc L. Rigas, Ph.D. National Exposure Research Laboratory, U.S. Environmental Protection Agency.
What Do Toxicologists Do?
Discussion Our current results suggest that it is possible to identify susceptibility regions using this methodology. The presented method takes advantage.
Pharmacokinetics & Pharmacodynamics of Controlled Release Systems Presented By: Govardhan.P Dept. of pharmaceutics, University College of Pharmaceutical.
Pharmacology in Nursing Men’s Health Drugs
Week 4 - Biopharmaceutics and Pharmacokinetics
PSY 853 PRESENTATION – Chapter 14 Anabolic-Androgenic Steroids.
1 Mechanism-based model of effect of co- administration of exogenous testosterone and progestogens on the hypogonadal axis in men Ashley Strougo (1), Jeroen.
The Intact Male Assay As An Alternative Tier I Screening Assay For Detecting Endocrine-Active Compounds John C. O’Connor DuPont Haskell Laboratory for.
Reproductive Hormonal Pharmacology Douglas Danforth, Ph.D. The Ohio State University.
ENDOCRINE SYSTEM Honors Biology. Introduction Glands that transmit chemical messengers throughout the body Hormones: chemical messengers –Circulate through.
The General Concepts of Pharmacokinetics and Pharmacodynamics Hartmut Derendorf, PhD University of Florida.
Animal Studies and Human Health Consequences Sorell L. Schwartz, Ph.D. Department of Pharmacology Georgetown University Medical Center.
EMEA London Pharmacokinetic- pharmacodynamic integration in veterinary drug development: an overview P.L. Toutain National Veterinary School ;Toulouse.
Predicting Subsequent Response to Hormone Therapy Following First-line Androgen Deprivation in Advanced Prostate Cancer S. Turner H. Gurney V. Gebski M.
Androgens & Antiandrogens Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University April 2014.
PHARMACOKINETIC MODELS
Objective: To utilize preclinical and phase I PK/PD data from a new quinolone (Q) and relevant public domain data to develop an exposure-response model.
MECHANISTIC MODEL OF STEROIDOGENESIS IN FISH OVARIES TO PREDICT BIOCHEMICAL RESPONSE TO ENDOCRINE ACTIVE CHEMICALS Michael S. Breen, 1 Miyuki Breen, 2.
Drug Administration Pharmacokinetic Phase (Time course of ADME processes) Absorption Distribution Pharmaceutical Phase Disintegration of the Dosage Form.
Model structure  Law of mass action applied to describe the reversible solifenacin-AGP, solifenacin-albumin and solifenacin-VBC binding  VBC positioned.
BASIC PHARMACOLOGY 2 SAMUEL AGUAZIM(MD).
The Hamner Institutes for Health Sciences | SOT Meeting March 9, 2011 Update on Formaldehyde Case Study: Adaptation of the Biologically Based Dose Response.
Androgenic Steroids Overall Organization of the Topic
Male sex hormones Androgens Types: 1.Natural androgens: – Androsterone and testosterone 2.Synthetic androgens: – Testosterone propionate. – Anabolic.
European Patients’ Academy on Therapeutic Innovation The key principles of pharmacology.
Properties of the Steady State. Sensitivity Analysis “Metabolic Control Analysis” Flux and Concentation Control Coefficients:
Androgens -Role in males similar to the of estrogens in females - development of male sexual characteristics - stimulating protein synthesis, growth of.
PHT 415 BASIC PHARMACOKINETICS
Oral Contraceptives Estrogen and Progestin. 2 Hormonal contraceptives Hormonal contraceptives contain either a combination of an estrogen and a progestin.
1 Biopharmaceutics Dr Mohammad Issa Saleh. 2 Biopharmaceutics Biopharmaceutics is the science that examines this interrelationship of the physicochemical.
1 CHAPTER 2 DEFINITIONS RELATED TO PHARMACOKINETICS.
The mean weight of normal prostate in adult male is about 11 gram (usually ranging between 7 & 16 gram). Some references state that the avarage weight.
TURNING PEPTIDES INTO DRUGS Background Materials & Methods 1) Bataille et al., FEBS Letters, 146, 79-86, ) Gros et al., Endocrinology, 133, ,
Physiology for Engineers
P356 Visceral fat drives 5alpha-reductase activity independent of body mass index in women with polycystic ovarian syndrome Punith Kempegowda1, Michael.
Fig. 1 UGT2B15 mRNA levels are stimulated by E2 in a time- and dose-dependent manner in MCF-7 breast cancer cells. A, Time course for E2 treatment. Cells.
Volume 67, Issue 6, Pages (June 2015)
Effects of chronic exposure to a high dose GnRH agonist (Deslorelin)
Regulation of lipogenesis in human hepatocytes by androgens, glucocorticoids and 5α-reductase. * N Nikolaou1, M Nasiri2, LL Gathercole1, S Parajes2, N.
…driving discovery An improved potent direct thrombin inhibitor shows efficacy with low bleeding risk Anirban Datta et al.
Figure 1. TAK-448 structure (A) and effect on the hypothalamic-pituitary-gonadal axis (B). At the normal physiological state, GnRH pulses in the hypothalamus.
Steroids & Muscle Growth
Hanneke van der Lee, MD, PhD
Shifting the Paradigm of Testosterone and Prostate Cancer: The Saturation Model and the Limits of Androgen-Dependent Growth  Abraham Morgentaler, Abdulmaged.
Androgenic Steroids Overall Organization of the Topic
Biopharmaceutics Dr Mohammad Issa Saleh.
Case for androgens Giorgio Arnaldi Clinica di Endocrinologia
Pharmacokinetics & pharmacodynamcs
Diabetes and Bone: the model of GIO
Endocrine disruptors and animal-free toxicology
Volume 67, Issue 6, Pages (June 2015)
therapy and to block androgen action
Michèle Algarté-Génin, Olivier Cussenot, Pierre Costa  European Urology 
Introduction to Pharmacology
William G. Nelson, Michael C. Haffner, Srinivasan Yegnasubramanian 
Nat. Rev. Urol. doi: /nrurol
Introduction to Pharmacology
unbound concentration µM
Presentation transcript:

BIOLOGICAL MODELS International Science Forum on Computational Toxicology May 21–23, 2007 Research Triangle Park, North Carolina Hugh A. Barton 1, Laura K. Potter 2,3, Michael G. Zager 1,2 1 U.S EPA, ORD, Computational Toxicology Research Program, 2 Curriculum in Toxicology, University of North Carolina-Chapel Hill; 3 National Health and Environmental Effects Research Laboratory, U.S., EPA, RTP, NC Prostate Regulation: Modeling Endogenous Androgens and Exogenous Antiandrogens Antiandrogens perturb hormonal regulation of the male endocrine system. Prostate function is a particularly sensitive response for androgen function. The dose-response characteristics of the system are not well characterized. Antiandrogens include both environmental and pharmaceutical compounds. Fungicides, such as vinclozolin and procimidone, and pharmaceutical agents, such as flutamide and bicalutamide are androgen receptor antagonists. Pharmaceutical inhibitors of 5  -reductase conversion of testosterone to dihydrotestosterone (DHT), include finasteride. Castration is a commonly used surgical hormonal perturbation. Research Goals Impact and Outcomes Results/Conclusions Science Question Develop a model for the androgenic regulation of prostate function in intact and castrate rats. Incorporate antiandrogen pharmacokinetics and perturbations of prostate function. Extend model with pubertal transition to evaluate dose-response in pubertal assays. The time course of prostate responses to androgen deprivation by castration or finasteride treatment is successfully reproduced by this combined biologically based pharmacokinetic and pharmacodynamic model. The model predicted data on prostate weight and blood flow that were not used in model parameter estimation (i.e., calibration). The model demonstrates the potential for using biologically based models to describe underlying biology and its perturbation by environmental or pharmaceutical compounds. Further developments are required to simulate the literature on androgen supplementation via silastic implants to calibrate the dose-response aspects of the model including for gene expression data. That will result in a predictive model for the adult that could then be extended to describe the hormonal changes associated with puberty, which would be useful for interpretation of pubertal assay results. References Potter, L.K., Zager, M.G., and Barton, H.A. (2006) A Mathematical Model for the Androgenic Regulation of the Prostate in Intact and Castrate Adult Male Rats. Am J Physiol Endocrinol Metab. 291(5):E Coyotupa J, et al. Endocrinology 92: , Johansson A, et al. Endocrinology 146: , Kyprianou N and Isaacs JT. Endocrinology 122: , Lee C. Prog Clin Biol Res 75A: , Lekas E, et al. Urol Res 25: , Ono Y, et al. Int J Androl Feb;27(1):50-6. Prins GS. J Steroid Biochem 33: , 1989 Rittmaster RS, et al. Endocrinology 136: , J. D. Stuart et al., Biochemical Pharmacology 62 (2001) Two-Compartment PK model for Finasteride Oral Dose Peripheral Compartment Central Compartment Elimination HoursDays Predicted Finasteride Concentration in Central Compartment (μM) Model parameters from J. D. Stuart et al., 2001 Pharmacodynamics: Prostate: Gene to Tissue Response Model Simulations: Time-Dependent Inhibition of Prostatic 5  - Reductase Type 2: T → DHT + Fin  5  R  Fin  5  R  Fin * Off rate set to zero 5R5R + T  5  R  T  5  R + DHT 5  -reductase isoforms Type 1: Located throughout the body, high in liver, low in prostate. Finasteride competes competitively with T for 5  -reductase type 1. Reversible enzyme inhibition. Type 2: High concentrations in prostate, low in most other tissues. Finasteride exhibits time-dependent inhibition of 5  -reductase type 2. Very slow off rate (~30 d). Virtually irreversible enzyme inhibition. Modeling Different Enzyme Inhibition Mechanisms for Finasteride Competitive Inhibition of Hepatic 5  - Reductase Type 1 : T → DHT Predicted Prostate Regression Following Castration: Model Calibration and Validation Days after castration Fraction of intact Prostate weight Lee 1981 Lekas et al Rittmaster et al Prins 1989 Serum T Kyprianou and Isaacs 1988 Coyotupa et al Serum DHT Coyotupa et al Prostatic AR Suzuki et al Cell mass Duct lumen mass Rittmaster et al Hours after castration Fraction of intact Validation: Prostate weight after castration Data: Johansson et al Data: Ono et al Model prediction Hours after castration Fraction of intact Validation: Prostatic blood flow after castration Data: Ono et al Model prediction Predicted Serum Hormone Concentrations after Simulated 0.02 nmol iv Dose of T Demonstrating Feedback Regulation T blood simulation nM Time (hours) LH blood simulation T testes simulation Pharmacokinetics: In addition to the pharmacokinetic models above for testosterone and DHT, the model incorporates a compartmental model for luteinizing hormone (LH). There is an empirical description of the feedback loop between LH and testosterone. Finasteride Challenge Data: Rittmaster et al., 1995 Experimental Conditions: 40 mg/kg Finasteride daily for 21 d, Reported: Hormone concentrations and prostate mass for intact, finasteride treated and castrated rats at days 4, 9, 14, 21 Prostatic T Days Concentration (nM) Prostatic DHT Concentration (nM) Days Prostate Mass (fraction of intact) Prostate Weight Days