Lecture 6: Metabolism Flashcards
Metabolism importance
-important determinant of duration and intensity
-alter activity of drugs
-influence half-life
-adverse drug effects
2 reasons metabolism is important in drug reactions
-accumulation
-toxic metabolite
Largest means of elimination of drugs
metabolism
Sites of drug metabolism
-liver
-GI tract
-lungs
-kidney
-brain
-skin
Liver
-smooth ER of liver cells
-high concentration of metabolizing enzymes
-first organ exposed to compounds from the gut
Sites of Metabolism before drug enters systemic circulation
-small intestine
-liver
Phase I of drug metabolism
-biotransformation to introduce or expose functional group for phase II reactions
-catalyxed by CYP using NADPH and oxygen
Phase I reactions
-oxidation
-hydroxylation
Phase II (Conjugation) of metabolism
-conjugation of polar group (acetyl, sulfate) with drug
-change charge and polarity
Phase I metabolites
-excreted if polar
-or functionalized to undergo phase II
Cytochrome P450
-membrane anchored
-heme group
-oxidation
-broad specificities
P450 reductase
-coenzyme
-uses NADPH to provide reducing factors to P450
2 ways to decrease CYP450 metabolism
-inhibit P450 reductase
-decrease NADPH
-decrease expression
Nomenclature of CYPs
CYP[family][subfam][gene]*[allele]
CYP2D6*1A
most important CYPs
-CYP3A4
-CYP2D6
-CYP2C8
P450 substrates
-vast spectrum of diverse structures
-makes drug development hard
Catalytic center of CYP450
-iron-heme cofactor
-iron binds to 4 N of heme, one thiolate ligand, or water in native state
Light absorption of CYP450
-450nm
-upon reduction and carbon monoxide binding
Reaction mechanism
- substrate binds
- 2 reducing equivalents
- product
-many places to interfere this cycle
-iron catalytic site
CYP450 inhibitors
-coordinate with iron to prevent metabolism
CYP reactions
-Aromatic hydroxylation (OH)
-N-dealkylation (lose CH3 on N)
-O-dealkylation (lose CH3 on O)
-N-oxidation (and O to NR3)
-sulfoxidation (add =O to S)
-deamination
Intrinsic factors determining CYP450 metabolism
-compund must enter binding site
-how does ligand bind
-how strong is binding
-reactivity of group in catalytic center
-accessibility of chemical group
Reversible Inhibtion of CYP450
-compete for active site
-similar to antagonist
Factors that determine binding strength
-coordination strength with heme
-hydrophobic contacts with binding site
-specific contacts with binding site residues
