Nuclear Receptors Flashcards
Variability of drug metabolism is a complicating factor in ? (3)
Drug development
Drug therapy
Toxicology
What is the major cause of adverse drug-drug interactions?
Inhibition and induction of CYP metabolism by environmental factors
2 elimination processes?
Metabolism
Excretion
2 types of excretion and examples for each?
Major : urine, bile
Minor : saliva, sweat, milk, other body fluids, exhalation
What type of compounds are better for oral absorption?
organic compounds
What polarity and ionization are best for absorption?
Low polarity
Low ionization
Lipophilic drugs are poorly excreted by the ____ and ____
kidney
liver
Metabolism increases _____ and ____ ________
polarity
water solubility
Deactivation?
Metabolite with less pharmacological activity
Bioactivation? What type of drug is involved?
Drugs that have more pharmacologically active or toxic metabolites
Prodrugs
First-pass effect?
Intestine has a significant metabolic capacity for some drugs
Major site for metabolism?
Liver
Most common CYP450 enzyme?
3A4
CYP450 enzymes have highest abundance in _____ and ______
liver
intestine
Activity of CYP3A is affected by what? (2)
This leads to ____ or ______ of the enzyme.
Drugs
Diet
Inhibition or induction
Two regions of the CYP3A4 gene?
Regulatory
Structural
What process does the structural part of CYP3A4 gene go through?
Transcription
Translation
Protein
Increased drug metabolism
What is the role of the regulatory region of CYP3A4?
It has various binding sites for _____ _____
Control rate of expression of structural component of gene
Transcription factors
What is a sensor/transducer useful for?
Senses drug/diet when it enters the body.
It then transduces the signal to produce a change in expression of CYP3A4
What gene superfamily fo the sensor/transducers belong?
Nuclear Receptor Gene Superfamily
NR gene superfamily are what kind of protein?
Ligand-activated transcription factors
NR1l’s are of greatest relevance to what type of metabolism?
Which two receptors are involved?
Xenobiotic
Pregnane X-receptor (PXR, NR1l2) and Constitutive Androstane Receptor (CAR, NR1l3)
The Pregnane X-receptor (PXR, NR1l2) has highest level of expression where? (2)
Liver
Intestine
Pregnane X-receptor (PXR, NR1l2) forms heterodimer with ______.
Is this active or inactive form?
Retinoid X-receptor (RXR ; NR2B)
Active
Pregnane X-receptor (PXR, NR1l2) resides in the ______ and is bound to target genes in which state?
Nucleus
Unliganded
Pregnane X-receptor (PXR, NR1l2) binds where in the promoter region of target genes?
Xenobiotic Responsive Enhancer Modules (XREM’s)
Two configuration of XREMs?
Direct : Consensus DR3
Everted : Consensus ER6
Drugs that are PXR ligands and induce CYP3A4? (9)
Phenytoin Rifampicin Dexamethasone Verapamil Lovastatin Carbamazepine Clotrimazole Nifedipine Hyperforin
PK consequences of induction of drug metabolism? (4)
Decreased bioavailability (1st pass metabolism)
Increased elimination (systemic metabolism)
Decreased plasma concentration
Increased plasma conc. of metabolites
PD consequences of induction of drug metabolism? (3)
Loss of therapeutic benefit
Increased adverse effects
If prodrug : enhanced/excessive pharmaco. activity
How are PXR and CYP3A4 similar? (2)
Expression patterns
Ligand diversity
Induction of CYP3A4 metabolism by PXR is what kind of response?
Adaptive