BIOCHEMISTRY AND PHARMACOKINETICS OF POTENT NONSTEROIDAL CYTOCHROME P450(17-ALPHA) INHIBITORS

Two potent non-steroidal inhibitors (CB7645 and CB7661) of human cytoc hrome P450(17 alpha) were tested for in vivo activity in WHT mice. The re were no signs of toxicity, but there was no effect on the androgen- dependent organs. The phamacokinetics and biochemistry of the compound s 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 mu M, res pectively, occurred after 2-4 h, both compounds were cleared rapidly ( terminal half-lives 2.7 and 3.3 h, respectively) and neither was detec table 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 th e substrate progesterone was lower at 4.3 nM. These data indicate that , for effective and continuous inhibition of the murine cytochrome P45 0(17 alpha), enzyme, higher peak levels of the compounds would be requ ired, and these levels would need to be maintained throughout the trea tment period. (C) 1997 Elsevier Science Ltd.