Phenoconversion
The activity of a person’s CYP-enzymes is partially determined by their genotype. Based on genetics, people can be categorized as poor, intermediate, extensive, or ultra-rapid metabolizer. Besides someone's genotype, other factors can also influence the activity of CYP-enzymes like drug-drug interactions, pathogenic conditions, age and lifestyle (particularly smoking), and - often overlooked - inflammatory aspects. These factors can induce or inhibit the enzymes, and therefore a person’s CYP-enzyme phenotype.
Thus, there can be a mismatch with the expected rate of drug metabolism when only a patient's genotype is taking into account. This mismatch between genotype expected metabolism rate, and the real capacity of drug metabolism ('phenotype') is called phenoconversion.
For example, when a patient categorized as a poor metabolizer for CYP1A2 starts smoking, the smoking may induce the activity of CYP1A2. Hence, the patient ought to be treated like an non-poor CYP1A2 metabolizer. Sometimes it is less clear to predict specific changes. In case of pregnancy, the activity of several CYP450 enzymes are increased, like CYP3A4 and CYP2D6, whereas others (e.g. CYP1A2) are decreased.
Predictions on a patient's metabolism rate can get increasingly complex, for instance if it concerns an elderly patient with hepatitis, who is also a heavy smoker and uses several drugs that interact with the CYP metabolism.
Budesonide is metabolised by CYP3A4 and certain PK parameters are affected in case a budesonide user is characterized as a poor metabolizer.
Which of the following statements is/are true?
When a patient's phenotype is characterized as an ultra-rapid metabolizer for budesonide....
Extra info: The metabolism of budesonide is increased in case of an ultra-rapid metabolizer. This results in lower plasma concentrations, less exposure of drug, and a shorter half life. The distribution of budesonide is not affected.
A patient uses metoprolol and is genetically characterized as an ultra-rapid metabolizer for CYP2D6, but his phenotype (metabolic rate) is actually much lower, showing comparable drug metabolism as a poor metabolizer. This mismatch can be attributed to phenoconversion. Which of the following aspects likely contribute to a decrease in metabolism rate, and therefore can (partially) explain the phenoconversion?
Extra info: Contributors: Hepatic CYP450 activity is reduced in case of liver disease. Fluoxetine causes a drug-drug interaction with metoprolol, as it is a potent inhibitor of CYP2D6. Non-contributors: Smoking is an inducer for CYP1A2, but does not affect CYP2D6. Activity of CYP2D6 is increased during pregnancy.
