title: Preclinical pharmacokinetic, toxicological and biomarker evaluation of SR16157, a novel dual-acting steroid sulfatase inhibitor and selective estrogen receptor modulator.
abstract: OBJECTIVE
  SR16157 is a novel dual-acting inhibitor of estrogen action that irreversibly inhibits the estrogen biosynthetic enzyme steroid sulfatase (STS) and releases the selective estrogen receptor modulator SR16137, which blocks the estrogen receptor. SR16157 is a promising agent for the endocrine therapy of breast cancer. We conducted preclinical in vivo toxicity evaluations to determine the maximum-tolerated dose (MTD), target organ(s) of toxicity, reversibility, dose-limiting toxicity, no observable adverse effect level (NOAEL), and toxicokinetics (TK) and to investigate a potential biomarker for use in SR16157 clinical trials.
  
  
  METHODS
  SR16157 was administered to female Fischer 344 rats or beagle dogs by oral gavage (po) or capsule. Intravenous (iv) groups were included for the determination of bioavailability. Endpoints evaluated included clinical observations, body weights, hematology, serum chemistry, pharmacokinetics, TK, pathology of tissues, and STS activity in liver, or peripheral blood mononuclear cells (PBMCs).
  
  
  RESULTS
  For rats, the MTD (i.e., the highest dose that did not cause lethality but produced toxicity) was 33 mg/kg/day (198 mg/m(2)/day), and the NOAEL was <10 mg/kg/day (60 mg/m(2)/day). For dogs, the MTD was estimated to exceed 10 mg/kg/day (200 mg/m(2)/day), and the NOAEL was estimated to be at or above 2.5 mg/kg/day (50 mg/m(2)/day).
  
  
  CONCLUSIONS
  Our studies demonstrate that SR16157 has excellent pharmacokinetic properties and an acceptable toxicological profile. Modulation of STS activity in PBMCs appeared to be a possible biomarker for use in future clinical trials of SR16157.
authors.affiliation: SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493, USA. linda.rausch@sri.com
authors.forename: Linda
authors.initials: L
authors.lastname: Rausch
authors.forename: Carol
authors.initials: C
authors.lastname: Green
authors.forename: Karen
authors.initials: K
authors.lastname: Steinmetz
authors.forename: Sue
authors.initials: S
authors.lastname: LeValley
authors.forename: Paul
authors.initials: P
authors.lastname: Catz
authors.forename: Nurulain
authors.initials: N
authors.lastname: Zaveri
authors.forename: Karen
authors.initials: K
authors.lastname: Schweikart
authors.forename: Joseph
authors.initials: J
authors.lastname: Tomaszewski
authors.forename: Jon
authors.initials: J
authors.lastname: Mirsalis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics* / Q000633:toxicity; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008297:Male; D009651:Norpregnatrienes / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D020845:Selective Estrogen Receptor Modulators / Q000493:pharmacokinetics* / Q000633:toxicity; D013045:Species Specificity; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors*
chemical_list: C526897:21-(2-N,N-diethylaminoethyl)oxy-7-methyl-19-norpregna-1,3,5(10)-triene-3-O-sulfamate; D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; D009651:Norpregnatrienes; D020845:Selective Estrogen Receptor Modulators; D043266:Steryl-Sulfatase