Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys.
OBJECTIVE
SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole), is a new candidate cancer chemopreventive agent under development. It was designed using computational modeling based on a naturally occurring indole-3-carbinol and its in vivo condensation products. It showed promising anti-cancer activity and its preclinical toxicology profile (genotoxicity battery and subchronic rat and dog studies) was unremarkable. However, it exhibited a very poor oral bioavailability (<1%) in both rats and dogs. Therefore, a study was initiated to develop and evaluate in dogs and non-human primates formulations with a more favorable oral bioavailability.


METHODS
Two formulations utilizing surfactant/emulsifiers, PEG400:Labrasol and Solutol, were tested in dogs and monkeys. Levels of SR13668 were measured in plasma and blood using a high-performance liquid chromatograph-tandem mass spectrometer system. Non-compartmental analysis was used to derive pharmacokinetic parameters including the bioavailability.


RESULTS
The Solutol formulation yielded better bioavailability reaching a maximum of about 14.6 and 7.3% in dogs and monkeys, respectively, following nominal oral dose of ca. 90 mg SR13668/m(2). Blood levels of SR13668 were consistently about threefold higher than those in plasma in both species. SR13668 did not cause untoward hematology, clinical chemistry, or coagulation effects in dogs or monkeys with the exception of a modest, reversible increase in liver function enzymes in monkeys.


CONCLUSIONS
The lipid-based surfactant/emulsifiers, especially Solutol, markedly enhanced the oral bioavailability of SR13668 over that previously seen in preclinical studies. These formulations are being evaluated in a Phase 0 clinical study prior to further clinical development of this drug.
Kapetanovic
Izet M
IM
Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Rm. 2116, Bethesda, MD 20892, USA. kapetani@mail.nih.gov
Muzzio
Miguel
M
Hu
Shu-Chieh
SC
Crowell
James A
JA
Rajewski
Roger A
RA
Haslam
John L
JL
Jong
Ling
L
McCormick
David L
DL
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002227:Carbazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005215:Fasting; D005989:Glycerides; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry
D000970:Antineoplastic Agents; D002227:Carbazoles; D005989:Glycerides; D009930:Organic Chemicals; C523402:SR 13668; C440220:Labrasol; D011092:Polyethylene Glycols