Question

Drug idiosyncrasies. Debrisoquine, a \(\beta\) -adrenergic blocking agent, has been used to treat hypertension. The optimal dose varies greatly \((20-400 \mathrm{mg} \text { daily })\) in a population of patients. The urine of most patients taking the drug contains a high level of 4 hydroxydebrisoquine. However, those most sensitive to the drug (about \(8 \%\) of the group studied) excrete debrisoquine and very little of the 4 -hydroxy derivative. Propose a molecular basis for this drug idiosyncrasy. Why should caution be exercised in giving other drugs to patients who are very sensitive to debrisoquine?

Short answer

Drug idiosyncrasy is due to genetic variations in CYP2D6. Poor metabolizers show sensitivity and need precaution with other drugs.

Step-by-step solution

Understanding Drug Metabolism

Debrisoquine is metabolized by liver enzymes, specifically cytochrome P450 2D6 (CYP2D6), to its metabolite 4-hydroxydebrisoquine. This process is crucial for the drug's excretion from the body.

Identifying Genetic Variation

The variation in drug metabolism can be explained by genetic polymorphisms in the CYP2D6 enzyme. Some individuals have non-functional or low-activity variants of CYP2D6, leading to poor metabolism of debrisoquine.

Explaining Drug Sensitivity

Individuals with poor CYP2D6 activity (about 8% of the population) are 'poor metabolizers', meaning they have higher levels of unmetabolized debrisoquine and are more sensitive to its effects due to slower elimination.

Cautious Use of Other Drugs

Patients who are poor metabolizers of debrisoquine are likely to have altered metabolism for other drugs processed by CYP2D6. This can lead to increased risks of side effects or toxicity, necessitating caution when administering other medications.

Key concepts

Cytochrome P450

Cytochrome P450 enzymes are vital players in the metabolism of various drugs. They are a family of enzymes found primarily in the liver, responsible for the oxidative breakdown of many substances, including medications. These enzymes ensure that drugs are properly metabolized and excreted from the body.
The Cytochrome P450 family consists of several isoenzymes, with CYP2D6 being one of the most important for drug metabolism. These enzymes help to convert lipophilic drug molecules into more water-soluble forms, facilitating their excretion through urine.

• Key in activating or deactivating drugs.
• Contribute to the pharmacokinetics of drugs - how drugs are absorbed, distributed, metabolized, and excreted.
• Variability in the Cytochrome P450 function can lead to different drug responses among individuals.

Genetic Polymorphism

Genetic polymorphism refers to the variation in DNA sequence among individuals, which can significantly influence how drugs are metabolized. In the case of drug metabolism, polymorphisms in the CYP2D6 gene can affect enzyme activity. This leads to different classifications of metabolizer phenotypes: poor, intermediate, extensive, and ultra-rapid metabolizers.
These genetic differences are why some people break down drugs quickly while others take longer. Poor metabolizers, for instance, might experience increased drug effects due to slower breakdown and elimination, as with debrisoquine.

• Variability in how enzymes like CYP2D6 function due to genetic variation.
• Influences drug effectiveness and risk of side effects.
• Understanding these variations can help tailor medication regimens for safer and more effective treatments.

CYP2D6

CYP2D6 is one of the key enzymes in the Cytochrome P450 family responsible for metabolizing approximately 25% of all pharmaceuticals. Debrisoquine, a drug used to treat hypertension, is primarily processed by the CYP2D6 enzyme. The metabolic pathway involves the conversion of debrisoquine into its metabolite, 4-hydroxydebrisoquine.
However, the activity of CYP2D6 can vary greatly among individuals due to genetic polymorphisms. Those with non-functional or low-activity variants are termed 'poor metabolizers'. This classification is crucial for understanding why some individuals are more sensitive to the effects of certain drugs.

• CYP2D6 affects how drugs like debrisoquine are processed, influencing dosage and effectiveness.
• Variations in CYP2D6 function necessitate personalized dosing to minimize adverse effects.
• Patients with reduced CYP2D6 activity require careful monitoring when prescribed CYP2D6-metabolized drugs.