1: Eur J Clin Pharmacol. 2008 Dec;64(12):1147-61. Epub 2008 Sep 2.

Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction.

Verbeeck RK.

School of Pharmacy, Catholic University of Louvain, Brussels, Belgium.
roger.verbeeck@uclouvain.be

The liver plays a central role in the pharmacokinetics of the majority of drugs. 
Liver dysfunction may not only reduce the blood/plasma clearance of drugs
eliminated by hepatic metabolism or biliary excretion, it can also affect plasma 
protein binding, which in turn could influence the processes of distribution and 
elimination. Portal-systemic shunting, which is common in advanced liver
cirrhosis, may substantially decrease the presystemic elimination (i.e.,
first-pass effect) of high extraction drugs following their oral administration, 
thus leading to a significant increase in the extent of absorption. Chronic liver
diseases are associated with variable and non-uniform reductions in
drug-metabolizing activities. For example, the activity of the various CYP450
enzymes seems to be differentially affected in patients with cirrhosis.
Glucuronidation is often considered to be affected to a lesser extent than
CYP450-mediated reactions in mild to moderate cirrhosis but can also be
substantially impaired in patients with advanced cirrhosis. Patients with
advanced cirrhosis often have impaired renal function and dose adjustment may,
therefore, also be necessary for drugs eliminated by renal exctretion. In
addition, patients with liver cirrhosis are more sensitive to the central adverse
effects of opioid analgesics and the renal adverse effects of NSAIDs. In
contrast, a decreased therapeutic effect has been noted in cirrhotic patients
with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is
no simple endogenous marker to predict hepatic function with respect to the
elimination capacity of specific drugs. Several quantitative liver tests that
measure the elimination of marker substrates such as galactose, sorbitol,
antipyrine, caffeine, erythromycin, and midazolam, have been developed and
evaluated, but no single test has gained widespread clinical use to adjust dosage
regimens for drugs in patients with hepatic dysfunction. The semi-quantitative
Child-Pugh score is frequently used to assess the severity of liver function
impairment, but only offers the clinician rough guidance for dosage adjustment
because it lacks the sensitivity to quantitate the specific ability of the liver 
to metabolize individual drugs. The recommendations of the Food and Drug
Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study
the effect of liver disease on the pharmacokinetics of drugs under development is
clearly aimed at generating, if possible, specific dosage recommendations for
patients with hepatic dysfunction. However, the limitations of the Child-Pugh
score are acknowledged, and further research is needed to develop more sensitive 
liver function tests to guide drug dosage adjustment in patients with hepatic
dysfunction.


PMID: 18762933 [PubMed - indexed for MEDLINE]

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