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S. Shimada, K. Mizuno, T. Koide, T. Ohshima, J. Matsumoto, Y. Hattori; The Prediction for Clinical Drug Interaction of Nipradilol by in vitro Enzyme Kinetic study . Invest. Ophthalmol. Vis. Sci. 2006;47(13):421.
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© ARVO (1962-2015); The Authors (2016-present)
To predict the drug–drug interaction of nipradilol, which has ß–blocking property with NO donating action and is commercially available for the treatment of glaucoma in Japan, the metabolic characteristic was investigated using human tissue.
[14C]nipradilol was reacted with cytochrome P450s (CYPs) and glutathione S–transferases (GSTs) which were drug metabolic enzymes in a fraction of human liver. Its metabolites were measured by Radio–HPLC assay and the kinetic parameters were calculated.
It was revealed that some metabolic enzymes metabolized nipradilol in the liver tissue. According to the kinetic parameters, the contribution rate of the metabolism was high due to denitration by GST, 4–hydroxylation by CYP2D6, deisopropylation by CYP1A2. The Km value for the metabolic reaction of nipradilol in the human microsome was from 11.9 to 22.2 µmol/L. In addition, there was no practical inhibition on the metabolic reaction via CYP1A2, 2C9, 2C19, and 3A4 (IC50>50 µmol/L). The IC50 for inhibition of CYP2D6 by nipradilol was 16.5 µmol/L, which was high enough in comparison with the plasma concentration of nipradilol (0.3 nmol/L) after the topical instillation at a clinical dose for the treatment of glaucoma.
These results indicate that nipradilol hardly causes a drug–drug interaction by concomitant administration and that genetic polymorphism will not affect the nipradilol metabolism in the clinical use for the treatment of glaucoma.
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