Biochemistry and pharmacokinetics of potent non-steroidal cytochrome P450(17alpha) inhibitors.
Two potent non-steroidal inhibitors (CB7645 and CB7661) of human cytochrome P450(17alpha) were tested for in vivo activity in WHT mice. There were no signs of toxicity, but there was no effect on the androgen-dependent organs. The pharmacokinetics and biochemistry of the compounds in mice were investigated. Following i.p. administration of 0.5 mmol/kg of CB7645 and CB7661, peak plasma levels of 13.4 and 3.4 microM, respectively, occurred after 2-4 h, both compounds were cleared rapidly (terminal half-lives 2.7 and 3.3 h, respectively) and neither was detectable at 24 h. CB7645 produced some decrease in plasma testosterone at 4 h, but this was not sustained. When tested in vitro against the WHT testicular enzyme, the CB7645 and CB7661 were competitive inhibitors with K(i) values of 10 and 13 nM, respectively. However, the K(m) for the substrate progesterone was lower at 4.3 nM. These data indicate that, for effective and continuous inhibition of the murine cytochrome P450(17alpha) enzyme, higher peak levels of the compounds would be required, and these levels would need to be maintained throughout the treatment period.
Barrie
S E
SE
Cancer Research Campaign Centre for Cancer Therapeutics at the Institute of Cancer Research, CRC Laboratory, Sutton, Surrey, UK.
Haynes
B P
BP
Potter
G A
GA
Chan
F C
FC
Goddard
P M
PM
Dowsett
M
M
Jarman
M
M
D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D006207:Half-Life; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011374:Progesterone / Q000378:metabolism; D011422:Propionates / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013737:Testis / Q000201:enzymology; D013739:Testosterone / Q000097:blood; D014018:Tissue Distribution
C096244:2-methyl-2-adamantyl 2-methyl-2-(3-pyridyl)propanoate; C107077:CB 7645; D011422:Propionates; D011725:Pyridines; D013739:Testosterone; D011374:Progesterone; D013254:Steroid 17-alpha-Hydroxylase; D000218:Adamantane; D007654:Ketoconazole