Phase I Lecture Flashcards
Adrian Monk?
Xenobiotics from plants, bacteria, animals, pills
- The role of metabolism and excretion are to get rid of these substances
- Most are modified to facilitate excretion and some are just excreted
Drug metabolism is?
Intended to be a detoxification mechanism for the body
- To inactivate or activate drugs
- Each drug metabolite must be considered as a new drug entity to the body with potential actions and toxicity
What does the study of drug metabolism serve to explainn?
Function and fate of the drug in the body
Ways to manipulate the metabolic process to develop better drugs and avoid drug-drug metabolic interactions
A fuller understanding of genetic differences that predispose certain individuals to have undesired effects or toxicity
What are the key drug metabolizing organs?
Liver and GI tract
Kidney, lung, nasal epithelia, or choroid plexus in the brain can also be depending on the substance and sometimes even blood plasma
Where are phase I oxidative enzymes predominantly localized?
The ER
Where are phase II oxidative enzymes located?
Cytosol
What happens in phase I?
Introduction of a polar functional group
Slightly increases water solubility
Highly lipophilic molecules will go through phase I
– P450 enzymes put the OH on it and flag it for phase II
- Usually involves oxygen and makes metabolites retain activity or more active
- Usually adds a reactive O or N group
What happens in phase II?
Attachment of highly polar groups (glucuronide, glutathione)
- Majorly increases water solubility
- Generally leads to inactive metabolites that are highly water soluble and excreted from the body
Glutathione forms?
Oxided: inactive
Reduced: active form
How does Glutathione become active?
PPP
- G6PDH mediates the first step and it is the first step that generate the first NADPH which is used to create the reduced form of glutathione
- – The electron comes from the NADPH to keep the glutathione levels high
Cyclophosphamide metabolism?
Converts it to an active species that alkylate DNA
– induces apoptosis in cancer cells with rapid turnover (cancer chemotherapy)
What do methotrexate and 5FU do?
Anticancer agents
- Block use of dTMP by the rapidly growing malignant cells
- Methotrexate is a folic acid analog that can be taken up into cells and polyglutamated to form active species
Rate and extent of metabolism of a drug depends on?
Factors related to the enzyme (affinity, specificity) and cofactors/cosubstrates
- Influence the plasma drug concentration and duration of action of a drug
What are phase I enzymes?
Oxidases
- Families 1, 2, and 3 are involved with drugs
- Flavin monooxygenase, alcohol DH, Aldehyde oxidase, MAO
Cytochrome P450 Enzymes?
In a reduced state (Fe2+) this enzyme can bind CO
NADPH reduces Fe3+ to Fe2+ (so oxygen can bind) and then a second electron reduces oxygen
Where is glucuronyltransferase located and what is it important for?
In close proximity to P450 in the smooth ER
– Allows rapid conversion between phase I and then straight to GT for phase II
How does the iron in heme work?
It changes between ferrous and ferric states
– In Hb it stays as ferrous (2+)
What are CYP P450s major areas of concern in drug therapy?
Inhibition of drug metabolism
Induction of drug metabolism
Genetic polymorphisms in population
What is the concern with inhibition of drug metabolism?
Drugs, dietary or environmental factors compete for the same drug metabolism enzyme
- May show saturation if inhibitor is a substrate
- Usually competitive inhibition
- May be allosteric in some cases
- Some isoforms accept multiple substrates in active sites
- Slow parent drug metabolism and can raise plasma concentration
What is the concern with induction of drug metabolism?
Some drugs, dietary substances and environmental factors can stimulate expression of genes and create additional drug metabolizing enzymes
- Binding to a nuclear receptor –> increase translation or transcription –> more P450 so more of activation or effect
- Cause more parent drug to be metabolized and lower the active drug concentration –> effect can be compromised
What is Rifampin?
Antibacterial
Not used alone bc bacteria develope resistance to it quickly but occasionally is used alone in TB
- Notorious for causing induction of P450 –> causes change over time –> make more P450
What happens when drugs can induce their own metabolism or metabolism of other substances?
Half-life changes over time
- Amount of drug can become less and less effective even though dose may not change
Can inhibition and induction occur at the same time?
Yes
- Process of inhibition of P450: binding to the molecule’s active site and inhibit the reaction that comes normally
- Process of induction of P450: doesn’t have anything to do with the active site so it does not interfere with inhibition; involves increasing transcription and translation (complexes with the nuclear receptor)
What is the concern with genetic polymorphisms in the population?
Variation in P450 expression can cause important implications for drug evaluation and testing in animals
