PMID- 22576690
OWN - NLM
STAT- MEDLINE
DCOM- 20120831
LR  - 20120511
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 41
IP  - 1
DP  - 2012 Jul
TI  - Pharmacokinetics, pharmacodynamics and metabolism of a novel anticancer agent for 
      prostate cancer.
PG  - 337-44
LID - 10.3892/ijo.2012.1442 [doi]
AB  - The objective of these studies was to examine the murine pharmacokinetics, 
      pharmacodynamics and metabolism of 
      (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (Indole 15), a novel tubulin 
      inhibitor for the treatment of cancer. We developed HPLC and LC/MS/MS assays to 
      quantitate Indole 15 and characterize its metabolites in vivo. Pharmacokinetic 
      studies were performed after intravenous (IV), oral (PO) and subcutaneous (SC) 
      administration of 10 mg/kg doses to male ICR mice. Urine and fecal samples were 
      also collected over a 72-h period to identify metabolites. Pharmacodynamic 
      studies were conducted by monitoring the tumor size change during a period of two 
      weeks in PC-3 tumor bearing mice after daily IV administration of Indole 15 at 
      doses of 0, 10, 50, 100 and 150 mg/kg. The pooled plasma concentration data after 
      administration via different dose routes was simultaneously fitted by a 
      two-compartmental model. Indole 15 was moderately well absorbed after PO and SC 
      administration, with a bioavailable fraction of 0.27 and 0.72, respectively. The 
      steady state volume distribution (Vss) and clearance (CL) were estimated to be 
      7.0 l/kg and 4.36 l/h/kg, respectively. The mean data of PC-3 tumor growth in 
      mice was fitted well by a transduction model using fixed plasma pharmacokinetics 
      as a driving function. Analysis of the metabolites in mice indicated that the 
      compound undergoes extensive oxidative metabolism with subsequent sulfation. 
      These studies demonstrate that favorable pharmacokinetic and pharmacodynamic 
      properties of Indole 15 offer hope for achieving pharmacological activity in 
      early clinical trials.
FAU - Yang, Jun
AU  - Yang J
AD  - Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 
      Columbus, OH 43210, USA.
FAU - Ahn, Sunjoo
AU  - Ahn S
FAU - Wu, Zengru
AU  - Wu Z
FAU - Hwang, Dong-Jin
AU  - Hwang DJ
FAU - Miller, Duane D
AU  - Miller DD
FAU - Dalton, James T
AU  - Dalton JT
LA  - eng
GR  - R01 DK065227-01/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120420
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 ((3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Indoles)
RN  - 0 (Tubulin Modulators)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/metabolism/*pharmacokinetics
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Drug Stability
MH  - Half-Life
MH  - Indoles/administration & dosage/metabolism/*pharmacokinetics
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred ICR
MH  - Microsomes, Liver/metabolism
MH  - Prostatic Neoplasms/*drug therapy/pathology
MH  - Tissue Distribution
MH  - Tubulin Modulators/administration & dosage/metabolism/*pharmacokinetics
MH  - Tumor Burden/drug effects
MH  - Xenograft Model Antitumor Assays
EDAT- 2012/05/12 06:00
MHDA- 2012/09/01 06:00
CRDT- 2012/05/12 06:00
PHST- 2012/02/17 00:00 [received]
PHST- 2012/03/29 00:00 [accepted]
PHST- 2012/05/12 06:00 [entrez]
PHST- 2012/05/12 06:00 [pubmed]
PHST- 2012/09/01 06:00 [medline]
AID - 10.3892/ijo.2012.1442 [doi]
PST - ppublish
SO  - Int J Oncol. 2012 Jul;41(1):337-44. doi: 10.3892/ijo.2012.1442. Epub 2012 Apr 20.