Irreversible CYP3A inhibition accompanied by plasma protein-binding displacement: a comparative analysis in subjects with normal and impaired liver function

• Published in: Clinical pharmacology and therapeutics Vol. 85; no. 3; p. 319
• Main Authors: Orlando, R, De Martin, S, Pegoraro, P, Quintieri, L, Palatini, P
• Format: Journal Article
• Language: English
• Published: United States 01.03.2009
• Subjects: Adult; Aged; Blood Proteins - metabolism; Cross-Over Studies; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Double-Blind Method; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Erythromycin - metabolism; Erythromycin - pharmacology; Humans; Liver - drug effects; Liver - enzymology; Liver - physiology; Liver Diseases - enzymology; Liver Diseases - physiopathology; Male; Middle Aged; Protein Binding - drug effects; Protein Binding - physiology; Quinine - metabolism; Quinine - pharmacology
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2008.216

In this study, quinine was used as a probe substrate and erythromycin as a prototypical irreversible inhibitor of CYP3A to ascertain whether, like reversible CYP inhibition, the magnitude of irreversible inhibition is also strictly dependent on the status of liver function. The effect of erythromycin on oral quinine disposition was studied in 10 healthy subjects and in 20 patients with cirrhosis of the liver who had varying degrees of liver dysfunction. This effect was shown to be the result of two types of interaction: (i) irreversible inhibition of CYP3A-mediated quinine metabolism, the extent of which proved to be independent of liver function, and (ii) displacement of quinine from plasma protein-binding sites, the magnitude of the displacement increasing dramatically as liver function worsened. Such an interaction causes limited increases in the total concentration of the displaced drug but disproportionate increases in its free concentration; the latter increases are magnified by liver dysfunction, thereby requiring that the monitoring of free drug concentrations be made mandatory.