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Pharmacokinetics, Biodistribution and Metabolism of a Novel Selective Androgen Receptor Modulator Designed for Prostate Cancer Imaging

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Pharmacokinetics, Biodistribution and Metabolism of a Novel Selective Androgen Receptor Modulator Designed for Prostate Cancer Imaging 213-222.qxd 13/11/2009 02:14 ÌÌ Page 213 INTERNATIONAL JOURNAL OF ONCOLOGY 36: 213-222, 2010 213 Pharmacokinetics, biodistribution and metabolism of a novel selective androgen receptor modulator designed for prostate cancer imaging JUN YANG1, ZENGRU WU1, DI WU1, MICHAEL V. DARBY2, SEOUNG SOO HONG3,4, DUANE D. MILLER3,4 and JAMES T. DALTON1,4 Divisions of 1Pharmaceutics and 2Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210; 3Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee; 4GTx, Inc., Memphis, TN 38163, USA Received August 4, 2009; Accepted September 14, 2009 DOI: 10.3892/ijo_00000492 Abstract. Knowledge of the presence and extent of disease 3 doses were further simultaneously fitted with a two-compart- plays a major role in clinical management of prostate cancer, mental model and the results were similar to those obtained as it provides meaningful information as to which therapy to from non-compartmental analysis. Biodistribution studies choose and who might benefit from this therapy. The wide using 125I-labeled S-26 indicated that it did not specifically expression of androgen receptor (AR) in primary and meta- target AR-rich tissue (e.g. prostate). A substantial amount of static prostate tumors offers a cellular target for receptor- radioactivity recovered from thyroid gland indicated the mediated imaging of prostate cancer. In our previous study, a release of free iodine. In metabolism studies, unchanged S-26 non-steroidal AR ligand, S-26 [S-3-(4-fluorophenoxy)-2- and its metabolites were detected in rat urine and fecal samples. hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide] Oxidation, de-iodination, hydrolysis, and sulfate conjugation showed promising in vitro pharmacological properties as an were the major metabolic pathways of S-26 in rats, with de- AR-mediated imaging agent, with high AR binding affinity iodination representing a unique metabolic pathway of S-26 and AR specificity. The overall goal of this study was to among other selective androgen receptor modulators. In characterize the in vivo metabolic and biodistribution profile conclusion, the extensive plasma clearance and de-iodination of S-26 in rats. Non-compartmental pharmacokinetic ana- of S-26 likely contribute to its lack of AR tissue selectivity lysis of S-26 in rat plasma showed that clearance (CL), in vivo. Future studies using metabolically stable ligands with volume of distribution (Vdss), and half-life (T1/2) of S-26 were less lipophilicity and higher AR binding affinity may repre- 0.30±0.07 l/h/kg, 1.44±0.33 l/kg, and 4 h, respectively, after sent a promising and rational approach for AR-mediated intravenous (i.v.) administration. Dose proportionality (1, 10 imaging. and 30 mg/kg) studies suggested that the pharmacokinetics of S-26 are dose-independent. The plasma concentrations of all Introduction Prostate cancer is the most commonly diagnosed cancer and _________________________________________ remains the second leading cause of death from cancer in American men (1). Procedures for reliable and accurate staging Correspondence to: Dr James T. Dalton, GTx, Inc., 3 North Dunlap of prostate cancer are essential in the management of prostate Street, Memphis, TN 38163, USA cancer. Androgen receptor (AR) is an important intracellular E-mail: [email protected] receptor, which mediates the pharmacologic effects of andro- gens and is involved in the progression of prostate cancer. Abbreviations: AR, androgen receptor; DHT, dihydrotestosterone; T, testosterone; SHBG, sex hormone binding globulin; PEG 300, AR is expressed in all stages of prostate cancer evolution, polyethylene glycol 300; Ki, dissociation equilibrium constant of including prostatic intraepithelial neoplasia (2), primary (3,4) the inhibitor; HPLC, high-performance liquid chromatography; LC- and metastatic disease (5,6), both before and after androgen MS, liquid chromatography-mass spectrometry; MS/MS, tandem ablation therapy. Even androgen-independent tumors express mass spectrometry; GI tract, gastrointestinal tract; CL, clearance; the AR (2). Metastatic prostate tumors expressing AR regard- AUC, area under the concentration-time curve; T1/2, elimination less of their sensitivity to hormonal therapy offer a cellular half-life; Vdss, volume of distribution at equilibrium; DES, diethyl- target for receptor-mediated imaging or treatment of advanced stilbrestil; ID/g, injected dose per gram of tissue prostate cancer. Chemicals that modulate AR activity can be divided into Key words: pharmacokinetics, biodistribution, metabolism, androgen four classes based on their structure (steroidal and non- receptor, prostate cancer steroidal) and function (androgenic and antiandrogenic). Non-steroidal antiandrogens, a major interest for the treatment 213-222.qxd 13/11/2009 02:14 ÌÌ Page 214 214 YANG et al: PHARMACOKINETICS, BIODISTRIBUTION AND METABOLISM OF S-26 of ‘androgen-dependent’ prostate cancer, have been used Animals. Male Sprague-Dawley rats, purchased from Harlan clinically for years. Over the past several years, we determined Biosciences (Indianapolis, IN), were kept on a 12-h light/dark many of the physicochemical and structural requirements for cycle in temperature and humidity controlled rooms. Animals high affinity AR binding by non-steroidal ligands (7,8). had access to food and water ad libitum. All animal studies Much of our research efforts have focused on characterization were reviewed and approved by the Institutional Animal Care of the in vivo pharmacologic activity and tissue selectivity of and Use Committee at The Ohio State University. aryl propionamide selective androgen receptor modulators (SARMs) in animal models of androgen-dependent disease Pharmacokinetic studies. Male Sprague-Dawley rats weighing (9-12). We completed extensive studies on the molecular and 195-238 g were used for pharmacokinetic studies. A catheter preclinical pharmacology of these compounds, advancing them was implanted in the right jugular vein of each rat 24 h prior from high affinity but metabolically labile ligands (13) to to dosing. Animals (n=15) were divided into 3 groups. The tissue-selective drugs with promising in vivo pharmacologic pharmacokinetics of S-26 were determined after an intra- activity (9,10,12,14-17). These studies on the structure- venous dose of 1 or 10 or 30 mg/kg via the jugular vein. activity relationships for AR binding and activation provide Dosing solutions were prepared by dissolving S-26 in a important information for rationally modifying the structures vehicle containing DMSO (5%, v/v) in PEG 300. Doses were of non-steroidal ligand to obtain novel compounds for AR delivered in a volume of 500 μl, and the jugular vein catheter mediated imaging of prostate cancer (18). Our previous studies was flushed three times with total of 500 μl of saline. Blood showed that non-steroidal AR ligands incorporating iodine in samples were collected prior to the dose and at 5, 10, 20, 40, either the A ring or B ring of the aryl propionamide pharma- 60, 120, 240, 480, 720, 1080 and 1440 min after drug adminis- cophore retain high binding affinity to the AR (18-21). In our tration. Blood samples were immediately centrifuged at previous report, S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl- 3,000 g for 10 min. The plasma fraction of each sample was N-(4-cyano-3-iodo-phenyl)-propionamide (referred to as S-26 transferred to a clean Eppendorf tube and stored at -20˚C hereafter as in ref. 18) was shown to exhibit favorable until analysis. properties for further development as an imaging agent for prostate cancer, i.e., high-AR binding affinity of 3.3 nM HPLC-UV analysis. HPLC analytical methods to determine (which is similar to testosterone), high specificity (does not the plasma concentration of S-26 were developed and vali- cross-react with other members of the steroid hormone receptor dated. An aliquot (100 μl) of each plasma sample was spiked family) and lack of binding to SHBG, a plasma protein that with 20 μl of an internal standard (a structural analog of S-26, binds steroids with high affinity (18). S-26 (Fig. 1) incorporates 75 μg/ml final concentration) and mixed well with 1 ml of an iodine group at the meta-position of the A aromatic ring, acetonitrile. After centrifugation at 12,000 x g, 4˚C for 5 min, which provides the opportunity to introduce varying isotopes the supernatant was collected and evaporated. The residues of iodine for research, therapeutic and diagnostic purposes. were reconstituted in 150 μl of mobile phase and an aliquot Iodine-125 offers a good radiotracer for imaging research, of 100 μl was used for HPLC analysis. The separation of S-26 whereas iodine-123 could be clinically used for diagnosis and internal standard was carried out using an isocratic mobile and iodine-131 could be used for receptor-mediated radiation phase (acetonitrile/H2O:50/50, v/v) at a flow rate of 1 ml/min therapy. Reported herein are the in vivo evaluations and with a Nova-Pak C18 column (3.9x150 mm, particle size 4 μm) characterization of S-26 as a potential AR mediated imaging (Waters Corporation, Milford, MA). The UV absorbance of agent. We first determined the pharmacokinetic parameters eluents was monitored at 270 nm. Calibration standards were of S-26 and then synthesized 125I-labeled S-26 for in vivo bio- prepared in blank rat plasma with concentrations ranging distribution studies in rats. As a whole, these studies provide from 0.05 to 50 μg/ml. The recovery of S-26 ranged from important new information regarding the metabolic and physico- 95.1 to 99.6%, as measured using low, medium and high chemical factors that govern AR-mediated accumulation of the concentration samples. The intra- and inter-day coefficients aryl propionamide SARMs and suggest structural modifications of variation of the assay were 5.2 and 8.5%, respectively, at a to improve their potential for prostate cancer imaging.
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