Abstract
NK-104 is a new and very potent competitive inhibitor of HMG-CoA reductase. NK-104 bound to plasma protein of mouse, rat, rabbit, dog and monkey, at a binding ratio of more than 96%. NK104 also highly bound to human serum albumin and a1 acid glycoprotein. However, no interaction in protein binding was found between NK-104 and selected highly protein binding drugs at their therapeutic concentrations in human plasma.
The in vitro metabolism of 14C-NK 104 was investigated using the liver microsomes of rat, rabbit, guinea pig, dog, monkey and human. The radioactivity was mostly due to unchanged NK-104 except for monkey. A relatively large amount of M-13 (8-hydroxy NK-104) was observed in monkey, but not in other animal species. The kinetic study of NK 104 metabolism suggested that M-13 was formed with relatively low intrinsic clearance. Based on three different in vitro approaches, namely 1) chemical inhibition, 2) immunoinhibition and 3) metabolism by recombinant human P450, it is concluded that CYP2C9 and CYP2C8 are the enzymes responsible for the metabolism of NK-104. In addition, no inhibitory effect on CYP mediated 4-hydroxylation of tolbutamide (CYP2C9) in the presence of NK-104 was detected.
In conclusion, NK-104 was highly bound to plasma protein whereas no mutual interaction in protein binding was found between NK-104 and various commonly used drugs. Furthermore, NK-104 was scarcely metabolized in the liver microsomes, and no drug/drug interaction between NK-104 and tolbutamide was noted in in vitro metabolism.
