The effects of etodolac (CAS 41340-25-4) on P450 isoform-specific activities in human hepatic microsomes were examined. Etodolac had little effect on 7-ethoxyresorufin O-deethylation (CYP1A2), coumarin hydroxylation (CYP2A6), 7-benzyloxyresorufin O-debenzylation (CYP2B6), S-mephenytoin hydroxylation (CYP2C19), bufuralol hydroxylation (CYP2D6), chlorzoxazone hydroxylation (CYP2E1) and nifedipine oxidation (CYP3A4) at concentrations ranging from 10 to 50 micromol/L. Etodolac inhibited tolbutamide hydroxylation (CYP2C9) with the Ki value of 64 micromol/L, suggesting that it is a weak inhibitor of CYP2C9. The in vivo drug interaction was predicted from the in vitro data using the [I]/([I] + Ki) value. Because the value was calculated to be almost 1, it is not likely that etodolac causes the drug interactions with the CYP2C9 substrates.
The effects of irsogladine (CAS 84504-69-8) on P450-isoform specific activities in human hepatic microsomes were examined. Irsogladine had little effects on coumarin hydroxylation (CYP2A6), 7-benzyloxyresorufin O-debenzylation (CYP2B6), S-mephenytoin hydroxylation (CYP2C19), bufuralol hydroxylation (CYP2D6), chlorzoxazone hydroxylation (CYP2E1) and nifedipine oxidation (CYP3A4) at concentrations ranging from 10 to 50 pmol/L. However, it inhibited 7-ethoxyresorufin O-deethylation (CYP1A2) and tolbutamide hydroxylation (CYP2C9) with the Ki values of 276 and 156 micromol/L, respectively. This suggests that it is a weak inhibitor of these isoforms. Because the plasma concentrations of irsogladine in humans are much lower than these Ki values, it is unlikely that irsogladine causes drug interactions with other drugs.
After a single oral administration of 1 mg/kg of 14C-NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide hydrochloride, CAS 137431-04-0), the radioactivity distribution in tissues of male pigmented rats was studied and compared with that in male albino rats. One eye of each pigmented rat was divided into melanin-containing structures (uvea, pigmented epithelium and sclera) and others without melanin (cornea and lens), and the radioactivity concentration in each ocular tissue was measured. In all the pigmented rat body tissues tested, maximum radioactivity concentrations (Cmax) were reached within 4 h after administration. At 1 h, the kidney showed the highest concentration (11 times the plasma concentration), followed by the urethra, liver, urinary bladder and lung. Concentrations in the other tissues were similar to or less than the plasma concentration. The radioactivity concentrations in most tissues decreased rapidly, being less than 10% of the Cmax 24 h after administration. These characteristics of the 14C-NS-49 tissue distribution in the pigmented and albino rats did not differ. In the eye, however, the radioactivity concentration decreased more slowly in the pigmented than in the albino rats. Most of the radioactivity in the eyes of the pigmented rats was present in melanin-containing structures indicating that NS-49 binds to ocular melanin. The radioactivity concentration in the melanin-containing structures reached a maximum 4 h after administration, then decreased as did that for the whole eye with a t1/2, beta of 66.8 h.
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