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Assessment of liver metabolic function. Clinical implications
1Institut für Klinische Pharmakologie, Universitätsklinikum Charité, Humboldt-Universität, Berlin, Germany.
Clinical Pharmacokinetics
|September 1, 1994
Summary
Liver function variability significantly impacts drug pharmacokinetics due to genetic factors and drug interactions. Enzyme-specific testing, analyzing metabolites, is superior to general liver function tests for accurate assessment.
Area of Science:
- Pharmacology
- Hepatology
- Biochemistry
Background:
- Inter- and intraindividual variability in drug pharmacokinetics is primarily driven by liver function, encompassing hepatic blood flow and metabolic capacity.
- Factors influencing liver function include liver disease, genetic variations in drug-metabolizing enzymes, and drug interactions like enzyme induction or inhibition.
- The complexity of drug-metabolizing enzymes necessitates enzyme-specific assessment rather than relying on general liver function tests.
Purpose of the Study:
- To highlight the limitations of traditional liver function tests.
- To emphasize the importance of enzyme-specific assessment of liver function.
- To discuss various methods for evaluating drug-metabolizing enzyme activity and genetic variability.
Main Methods:
- Utilizing specific probe substrates to assess individual drug-metabolizing enzyme activities (e.g., cytochrome P450 enzymes).
- Employing the 'cocktail approach' with multiple test substances or the 'metabolic fingerprint approach' analyzing multiple metabolites of a single substance.
- Quantifying enzyme activity through in vivo and ex vivo enzymological methods, Western blot analysis, mRNA quantification, and molecular genetic methods.
Main Results:
- Enzyme-specific analysis, particularly metabolite analysis, offers a more accurate reflection of liver function compared to parent drug clearance.
- Specific methods exist to quantify the activity of major cytochrome P450 and phase II enzymes.
- Molecular genetic methods can classify individuals based on their metabolic capacity (poor, extensive, or intermediate metabolizers).
Conclusions:
- Traditional liver function tests have limitations; enzyme-specific testing is crucial for understanding drug pharmacokinetics.
- Assessing genetic variability in drug-metabolizing enzymes is essential for predicting drug response and variability.
- Therapeutic drug monitoring implicitly assesses relevant enzyme activities, and novel methods offer precise characterization of liver function and genetic predispositions.