Drug Metabolism Flashcards
What does metabolism tend to do to a drug?
Metabolism tends to eliminate or reduce the pharmacological and toxicological activity of a drug.
Increase polarity and solubility so that it can more easily be excreted.
What is hepatic first pass metabolism?
Metabolic conversion of the drug in the liver, into something that is different before the drug enters the circulation.
What effect does extensive first pass metabolism have on bioavailability?
Lowers bioavailability
How can you avoid hepatic first pass metabolism?
Administer Intravenously
What are the three types of reaction that fall under phase I reactions?
Oxidation
Reduction
Hydrolysis
What is the purpose of Phase I metabolism?
It is meant to release (redox) or unmask (hydrolysis) functional groups that can be used in phase II reactions
How do phase I reactions affect polarity of the drug?
They have little effect on the drug polarity
What enzyme system is extremely important to drug metabolism? Where are these enzymes found?
Cytochrome P450 It is a family of 57 (Like Heinz) enzymes that are mainly found in the liver and they are capable of metabolising many xenobiotics
What are the substrates and products of the Cytochrome P450 mediated oxidation reaction?
Substrates = drug, NADPH, oxygen (O2), protons (H+) Products = hydroxylated drug, NADP+, water
What do P450 enzymes have in their catalytic site?
They all have a porphyrin ring and an iron group (Fe3+)
Describe the oxidation cycle of Cytochrome P450.
Drug binds to iron in catalytic site of CYP450 e- donated from NADPH, reducing Fe3+ to Fe2+
Molecular oxygen binds to catalytic site, reduced into unstable form and oxidises Fe2+ to Fe3+
Second e- donated by NADPH, reducing Fe3+ to Fe2+, this FURTHER reduces Oxygen, instability leads to conversion of the drug to the hydroxylated derivative.
Reactive oxygen gains 2H+ becomes H2O
The drug is released and P450, along with its Fe3+, is ready to undergo another cycle
What is N-demethylation? What does this reaction produce?
This is the oxidation of a methyl group attached to Nitrogen, producing formaldehyde (HCHO), this removes the pharmacological activity of a drug
What is O-demethylation?
Oxidative attack of P450 on a methyl group attached to oxygen. This converts oxygen to the hydroxyl group and release formaldehyde (HCHO)
What is N-oxidation? Describe the type of bond formed.
It is the oxidation of the nitrogen group itself by Flavin containing monooxygenase (FMO)
Nitrogen has two free electrons that can form a dative bond with oxygen, generating an amino oxide
Describe a condition involving Flavin containing monooxygenase?
Trimethylaminuria (fish odour syndrome) is a deficiency of FMO.
Trimethylamine smells and is produced in the GI tract as a product of protein metabolism. It is converted to odourless itrimethylamine N-oxide by hepatic FMO, ready for excretion. Without FMO, Trimethylamine builds up leading to odour of ‘rotting fish’
