The effect of liver disease on inhibitory and plasma protein-binding displacement interactions: an update.
BACKGROUND
Inhibition of CYP-mediated metabolism is the most frequent and dangerous drug interaction, which causes serious problems in drug development, drug approval and clinical practice. The wide interindividual variability in the magnitude of such interactions constitutes the main hurdle to their management by dose adjustment.


METHODS
This review focuses on a recently identified source of variability in the extent of inhibitory drug interactions, namely liver functional status. It examines the differential effect of liver dysfunction on reversible and mechanism-based CYP inhibition, as well as on inhibition accompanied by plasma protein-binding displacement.


RESULTS
Liver disease progression is accompanied by a proportional, drastic reduction in the magnitude of reversible inhibitory drug interactions due to decreased hepatic uptake of the inhibitor and reduced CYP expression. The degree of mechanism-based inhibition is reduced to a much lesser extent as it is only influenced by the decreased hepatic content of the inhibited CYP enzyme. Metabolic inhibition accompanied by plasma protein-binding displacement results in a disproportionate rise in free drug concentration, the extent of which increases as liver function worsens.


CONCLUSIONS
For an appropriate management of inhibitory drug interactions, the patient's liver functional status and the mechanism of inhibition must be taken into consideration.
Palatini
Pietro
P
University of Padova, Department of Pharmacology and Anesthesiology, Largo E. Meneghetti 2, 35131 Padova, Italy. pietro.palatini@unipd.it
Orlando
Rocco
R
De Martin
Sara
S
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D004347:Drug Interactions; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008107:Liver Diseases / Q000503:physiopathology*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding
D001798:Blood Proteins; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System