Murine toxicology and pharmacokinetics of novel retinoic acid metabolism blocking agents.
OBJECTIVE
Novel potent C-4 azolyl retinoic acid metabolism blocking agents (RAMBAs)-VN/14-1, VN/50-1, VN/66-1, VN/67-1, and VN/69-1, have been synthesized and investigated for their in vitro and in vivo effects against breast and prostate cancers. These RAMBAs, in addition to being potent inhibitors of all-trans-retinoic acid (ATRA) metabolism have potent anti-cancer properties and in vivo anti-tumor efficacies as characterized in breast and prostate cancer models. Here we determined the toxicity and pharmacokinetics (PK) of these various RAMBAs.


METHODS
Preliminary acute toxicity studies of these RAMBAs were carried out using Swiss NIH mice. The toxicity profile of the RAMBAs was evaluated relative to ATRA. Three different doses (8.3, 33, and 100 micromol/kg/day) of ATRA and RAMBAs were administered on a daily basis subcutaneously for 14 days to the mice. Clinical signs of toxicity alopecia, scaly skin, and loss of body weight in the mice were observed during the study and the maximum tolerated dose was determined. PK of selected agents (VN/14-1, VN/50-1, and VN/66-1) was studied in Balb/C mice after a single dose subcutaneous administration. Plasma concentrations of the agents were quantitatively determined using a high-performance liquid chromatographic method with ultraviolet detection. Plasma concentration versus time profiles were fit to various PK structural models and relevant PK parameters were estimated.


RESULTS
VN/66-1 and VN/69-1 were found to be the least toxic even at the highest doses when compared to the other RAMBAs and ATRA. VN/66-1 had the longest half-life, the slowest clearance, and the greatest exposure.


CONCLUSIONS
Based on PK characteristics and toxicity studies, VN/66-1 appeared to be the most favorable agent. However, both VN/14-1 and VN/66-1 are our leads based on the fact that VN/14-1 has been found to be highly effective in endocrine-sensitive and -resistant breast cancer cells and tumors with little toxicity. Our findings provide valuable information that will be used to select RAMBAs and establish therapeutic regimens that provide optimal efficacy with minimal toxicity.
Patel
Jyoti B
JB
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD 21201-1559, USA.
Khandelwal
Aakanksha
A
Chopra
Pankaj
P
Handratta
Venkatesh D
VD
Njar
Vincent C O
VC
D000505:Alopecia / Q000139:chemically induced; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D007279:Injections, Subcutaneous; D051379:Mice; D008807:Mice, Inbred BALB C; D012871:Skin Diseases / Q000139:chemically induced*; D014018:Tissue Distribution; D014212:Tretinoin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity
C496751:4-(1H-imidazol-1-yl)retinoic acid; D000970:Antineoplastic Agents; D007093:Imidazoles; D014212:Tretinoin