Metabolism - The Pharmacokinetics Series

Summary

In this video, Jessica discusses drug metabolism as part of the pharmacokinetics series. She explains that metabolism, primarily occurring in the liver, transforms drugs into more water-soluble forms for excretion. Some drugs convert from active to inactive forms, while others activate from prodrugs. Metabolism is divided into two phases: Phase 1 (cytochrome P450 enzymes) and Phase 2 (conjugation reactions). Jessica highlights the importance of understanding drug interactions with these enzymes, particularly CYP3A4, CYP2D6, and others, which can impact drug efficacy and safety. The video wraps up with key examples of enzyme inducers and inhibitors affecting various medications.

Takeaways

• 📽️ Metabolism is the liver's contribution to drug clearance, making drugs more water-soluble for excretion.
• 💊 Drugs usually convert from active substances to inactive metabolites during metabolism, but some prodrugs activate through this process.
• 🧬 Phase 1 of metabolism involves modification, primarily governed by cytochrome P450 enzymes.
• 🔬 CYP enzymes are responsible for 75% of all drug metabolism, with genetic variability affecting their function.
• ⚠️ Inducing or inhibiting CYP enzymes can lead to significant drug interactions, affecting concentrations of active or inactive forms.
• 🧪 Phase 2 involves conjugation reactions, making drugs more water-soluble and ready for excretion, but can become saturated in toxic cases.
• ⚙️ The five main CYP enzymes for drug metabolism are CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2C19.
• ⚡ Inducers of CYP enzymes speed up metabolism, while inhibitors slow it down, potentially leading to toxicity or reduced drug effectiveness.
• 🚨 Notable interactions include macrolides inhibiting CYP3A4 (risking rhabdomyolysis with simvastatin) and fluoxetine inhibiting CYP2D6 (increasing side effects of risperidone).
• 📚 It's crucial to know if your drug is a substrate, inducer, or inhibitor of CYP enzymes, and the Flockhart table is a useful resource for this.

Q & A

What is the main goal of drug metabolism?

The main goal of drug metabolism is to make the drug more water-soluble so that it can be excreted from the body.

How are drugs typically converted during metabolism?

Drugs are usually converted from an active substance to inactive metabolites, although some drugs (like prodrugs) are converted from inactive forms to active ones.

What are prodrugs, and how do they relate to metabolism?

Prodrugs are inactive drugs that become active after metabolism. They are not cleared by the liver until after they are metabolized into their active form.

Why is cytochrome P450 important in drug metabolism?

Cytochrome P450 is important because it governs Phase 1 metabolism, responsible for breaking down drugs through oxidation, reduction, or hydrolysis. It accounts for 75% of all metabolism.

What is the significance of genetic variability in cytochrome P450 enzymes?

Genetic variability in cytochrome P450 enzymes can influence how individuals metabolize drugs, which affects drug interactions and the effectiveness of treatment.

What are the two phases of metabolism, and what happens in each?

Phase 1 is the modification phase, governed by cytochrome P450, which involves breaking down drugs. Phase 2 is the conjugation phase, where drugs are made more water-soluble for excretion.

Which five CYP enzymes are responsible for the majority of Phase 1 metabolism?

The five key CYP enzymes are CYP3A4, CYP2D6, CYP2C9, CYP1A2, and CYP2C19.

What happens when CYP enzymes are induced or inhibited?

Inducing CYP enzymes speeds up drug metabolism, resulting in lower drug concentrations. Inhibiting CYP enzymes slows metabolism, leading to higher drug concentrations and potential toxicity.

Why is it important to check if a drug is a substrate, inducer, or inhibitor of CYP enzymes?

It's important because drug interactions can occur, affecting how drugs are metabolized and potentially leading to reduced efficacy or increased toxicity.

Can you give an example of a notable CYP3A4 drug interaction?

Clarithromycin and erythromycin (strong CYP3A4 inhibitors) can raise serum levels of simvastatin, which could cause rhabdomyolysis. On the other hand, carbamazepine (a CYP3A4 inducer) may lower the effectiveness of birth control pills, leading to unintended pregnancy.