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.

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Absorption, distribution and protein binding of ¹⁴C-telmisartan (BIBR 277 SE) were investigated in rats after a single oral administration.
1. After oral administration of ¹⁴C-telmisartan (1 mg/kg) to fasted rats, the radioactivity was absorbed rapidly in both male and female rats, and the maximum plasma level (C_max) of 184.79-250.55 ng eq./ml was reached within 1 hr. Elimination half-lives (t_{1/2 (8-24hr)}) in male and female rats were about 7 hr. The plasma level-time profiles in males and females were similar.
2. The effect of food intake on the drug absorption in male rats was investigated. The C_max and AUC_(0-48hr) were about 37% and 77% of those of fasted rats, respectively. The absorbed amount of ¹⁴C-telmisartan after oral administration was thus slightly decreased by food intake.
3. The ligated loop method was used to examine the absorption sites. Absorption ratios in the stomach at 30, 60 and 120 min after administration were 12.5, 28.3 and 24.2%, respectively. Those in the duodenum, the jejunum, the ileum and the colon at 30, 60 and 120 min after administration were 43.1-61.9, 43.9-78.5 and 79.4-86.3%, respectively. These findings suggested that ¹⁴C-telmisartan is readily absorbed throughout the gastrointestinal tract, except the stomach.
4. Radioactivity in tissues after oral administration of ¹⁴C-telmisartan (1 mg/kg) to fasted male rats was investigated. Radioactivity in most tissues peaked at 0.5 hr after administration. High levels of radioactivity were observed in the liver and gastrointestinal tract, including its content. The central nervous system showed only a low radioactivity content. The levels of radioactivity in tissues rapidly decreased with time. Thus, there was no marked accumulation of radioactivity in any tissue.
5. Distribution of radioactivity into blood cells was low at all sampling points after administration. The in vivo plasma protein binding of radioactivity was very high, being greater than 99% at 30 min after administration.

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Plasma concentration and distribution of ¹⁴C-telmisartan after repeated oral administration at a dose of 1 mg/kg given once a day for 7 days to fed male rats were investigated.
1. The pharmacokinetic parameters of ¹⁴C-telmisartan in plasma were as follows. The C_max t_1/2(12-48hr), AUC_(0-48hr) and MRT_(0-48hr) values of ¹⁴C-telmisartan in plasma after the final administration was 61.95 ng eq./ml, 12.76 hr, 1529.33 ng eq.·hr/ml and 14.85 hr, respectively. Plasma levels of radioactivity peaked at about 7 hr after the final administration. The levels of radioactivity in plasma before each administration (trough value) for 7 days did not increase with increasing number of administrations. The radioactivity profile in plasma after the first and final administrations was very similar.
2. Radioactivity levels in tissues after 7-day repeated oral administration decreased with time. The levels of radioactivity in all tissues were lower than the plasma levels at all sampling points, except in the gastrointestinal tract, including its content, liver, kidney and lung. Radioactivity in the liver was eliminated in parallel with that in plasma, and the other tissue levels had become undetectable at 72 hr or 168 hr. The distribution pattern of radioactivity was very similar to that after a single administration to fasted male rats.
3. From 4 hr to 72 hr after administration, the ratio of the concentration in blood cells to that in plasma was in the range of 0.1-0.3. There was little distribution of radioactivity to blood cells, in agreement with the finding after a single oral administration.

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