Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction |
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Authors: | Roger K Verbeeck |
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Institution: | (1) School of Pharmacy, Catholic University of Louvain, Brussels, Belgium;(2) School of Pharmacy, UCL/PMNT 7369, Av. E. Mounier 73, B-1200 Brussels, Belgium |
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Abstract: | 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 β-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. |
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Keywords: | Drug dosage adjustment Hepatic dysfunction Liver disease Drug clearance Pharmacokinetics |
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