caa a22 4500 605533970 CHVBK 20210128100840.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s10928-015-9421-5 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9421-5 Pharmacokinetics and pharmacodynamics of 3,3′-diindolylmethane (DIM) in regulating gene expression of phase II drug metabolizing enzymes [Elektronische Daten] [Tien-Yuan Wu, Ying Huang, Chengyue Zhang, Zheng-Yuan Su, Sarandeep Boyanapalli, Tin Khor, Hu Wang, Hongxia Lin, Murugesan Gounder, Leonid Kagan, Ioannis Androulakis, Ah-Ng Kong] 3,3′-Diindolylmethane (DIM) has been investigated as a potential anti-cancer chemopreventive agent in many preclinical and clinical studies. In this study, we sought to characterize the pharmacokinetics of DIM and to build a pharmacokinetic (PK) and pharmacodynamic (PD) model of the DIM-induced gene expression of phase II drug metabolizing enzymes (DME), which potentially links DIM's molecular effects to its in vivo chemopreventive efficacy. DIM (10mg/kg) was administered intravenously (i.v.) to male Sprague-Dawley rats and blood samples were collected at selected time points for 48h. The plasma concentration of DIM was determined using a validated HPLC method. The mRNA expression of NQO1, GSTP1 and UGT1A1 in blood lymphocytes was measured using quantitative PCR. An indirect response model was employed to relate the concentration of DIM to the expression of the genes NQO1, GSTP1 and UGT1A1, which were chosen as PD markers for DIM. After i.v. administration, the plasma concentration of DIM declined quickly, and the expression of target genes increased significantly, peaking at 1-2h and then returning to basal levels after 24h. The parameters in the PK-PD model were estimated. The PK-PD model aptly described the time delay and magnitude of gene expression induced by DIM. Our results indicate that DIM is effective at inducing various phase II DME, which are capable of detoxify carcinogens. This PK-PD modeling approach provides a framework for evaluating the acute effects of DIM or other similar drugs in clinical trials. Springer Science+Business Media New York, 2015 Diindolylmethane nationallicence Phase II metabolizing enzymes nationallicence Pharmacokinetics nationallicence Pharmacodynamics nationallicence Wu Tien-Yuan Department of Pharmacology, Tzu Chi University, Hualien City, Taiwan aut Huang Ying Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut Zhang Chengyue Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut Su Zheng-Yuan Center for Cancer Prevention Research and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut Boyanapalli Sarandeep Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut Khor Tin Center for Cancer Prevention Research and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut Wang Hu Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut Lin Hongxia Pharmacokinetics and Pharmacodynamics Shared Resource, The Cancer Institute of New Jersey, New Brunswick, NJ, USA aut Gounder Murugesan Pharmacokinetics and Pharmacodynamics Shared Resource, The Cancer Institute of New Jersey, New Brunswick, NJ, USA aut Kagan Leonid Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut Androulakis Ioannis Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut Kong Ah-Ng Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, 08854, Piscataway, NJ, USA aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/4(2015-08-01), 401-408 1567-567X 42:4<401 2015 42 10928 https://doi.org/10.1007/s10928-015-9421-5 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9421-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wu Tien-Yuan Department of Pharmacology, Tzu Chi University, Hualien City, Taiwan aut NATIONALLICENCE 700 1- Huang Ying Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Zhang Chengyue Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Su Zheng-Yuan Center for Cancer Prevention Research and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Boyanapalli Sarandeep Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Khor Tin Center for Cancer Prevention Research and Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Wang Hu Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Lin Hongxia Pharmacokinetics and Pharmacodynamics Shared Resource, The Cancer Institute of New Jersey, New Brunswick, NJ, USA aut NATIONALLICENCE 700 1- Gounder Murugesan Pharmacokinetics and Pharmacodynamics Shared Resource, The Cancer Institute of New Jersey, New Brunswick, NJ, USA aut NATIONALLICENCE 700 1- Kagan Leonid Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Androulakis Ioannis Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA aut NATIONALLICENCE 700 1- Kong Ah-Ng Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, 08854, Piscataway, NJ, USA aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/4(2015-08-01), 401-408 1567-567X 42:4<401 2015 42 10928