Abstract
This article reviews the influence of liver functional status on pharmacokinetic interactions due to inhibition and induction of drug-metabolizing enzymes. Recent human studies have shown that the magnitude of inhibitory interactions caused by the reversible CYP1A2 inhibitor fluvoxamine decreases as liver function worsens, and virtually vanishes in patients with more advanced hepatocellular insufficiency. This effect of liver dysfunction is independent of the pharmacokinetic characteristics of the CYP1A2 substrate, since it has been observed with both high- and low-clearance drugs. It is most probably due to reduced uptake of the inhibitory drug by the cirrhotic liver. In order to ascertain whether this is a general phenomenon, the following questions remain to be addressed: 1) whether the inhibition of any CYP isoform is reduced in liver disease; 2) whether the effect of liver dysfunction depends on the chemical nature of the inhibitory drug, since both reduced in vivo inhibition and in vitro uptake by the cirrhotic liver have so far been shown only for basic drugs; 3) lastly, if similar effects can also be observed with irreversible and quasi-irreversible inhibitors, as their accumulation kinetics in the hepatocyte may differ from those of a reversible inhibitor. Although many in vivo and in vitro studies have examined the inducibility of drug-metabolizing enzymes in liver disease, available data are incomplete and conflicting, since both well-preserved and severely curtailed responses to inducing agents have been reported. The reasons for these variable responses are most probably methodological, i.e., differences in the type and degree of liver dysfunction of the animals and patients examined, and in the type and dosage of the inducing agent used. Nonetheless, the results of those few studies which used pathologically homogeneous animal or patient groups suggest that, like basal enzyme expression, drug-inducible expression is also substantially preserved in mild to moderate liver disease, whereas it is lost in severe hepatic dysfunction. For a definitive conclusion, further studies are necessary which examine etiologically homogeneous patient groups and stratify patients rigorously according to their functional hepatic reserve. Such studies should also examine inducers with different physicochemical properties and acting by different mechanisms, since the expression of both hepatic transporters and nuclear receptors may be differentially affected by liver function impairment.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.