Drug Metabolism Flashcards
Name the primary organ involved in drug metabolism
liver
Smooth ER of liver cells
High concentration of drug metabolizing enzymes
Phase 1 metabolism
Biotransformation of xenobiotics (a compound foreign to the body) that includes oxidation, hydroxylation, and related changes that either introduce or expose a functional group
Typically catalyzed by CYP450 monooxygenases utilizing NADPH and oxygen
Phase 2 metabolism
Biotransformation of xenobiotics that involves conjugation with a polar group (e.g., sulfate, glucuronic acid) yielding a polar metabolite that can be more readily excreted in the bile or urine. These pathways are sometimes referred to as conjugation reactions and can be influenced by the availability of the co-substrate (e.g.,
sulfate or activated sulfate)
UGT are the most dominant Phase 2 enzymes. UGT and P450 are co-localized on ER.
Increases molecular size and polarity
Differentiate between Phase 1 and Phase 2 metabolism
Phase II metabolism frequently, but not always, occurs subsequent to Phase I metabolism. Some drug molecules are conjugated (undergo Phase II) without prior
metabolism
Match the primary substrates, inhibitors, and inducers of CYP3A4, CYP2D6, and
CYP2C9.
CYP3A4: substrates: midazolam, indinavir
Inhibitors: ritonavir, ketoconazole
Inducers: rifampin, St. John’s Wort
CYP2D6: substrates: codeine, fluoxetine
Inhibitors: fluoxetine, quinidine
Inducers: ?? clinical relevance
CYP2C9: substrates: S-warfarin, ibuprofen
Inhibitors: fluconazole, amiodarone
Inducers: rifampin, secobarbital
Given a specific CYP450, identify the family, subfamily, individual gene, and
allelic variant component.
Example: CYP2D6 * 1A
Family: 2
Subfamily: D
Individual gene: 6
Allele: 1A
Reversible Inhibition
Reversible inhibitors of CYP450 compete with substrate for binding at the active site. Nitrogenous compounds that can serve as the sixth axial ligand for iron in the heme are especially potent inhibitors of CYP450
Factors that determine binding strength:
Coordination strength with heme iron 4 bound to Nitrogen
Hydrophobic contacts with binding site of CYP
Specific contacts with binding site residues
Explain why genetic variation in metabolism often is not the most important factor
in determining variation in drug concentrations.
While genetic variation can be important as a determinant of the variability of drug
metabolism, other sources of variability (diet, other drugs, disease, environmental
exposures, etc) are often more important than genetics variation
Describe the catalytic center of CYP450
active site of CYP contains an iron-heme cofactor coordinated to four nitrogen atoms of the heme, to one thiolate ligand derived from cysteine.
Mechanism-based inhibition
also known as suicide inhibition
are metabolized to reactive species which covalently bind to the heme or binding site
residues on the CYP450 protein. This covalent binding renders the CYP450 inoperable and new CYP450 must be synthesized for restoration of normal metabolism
Induction Mechanism
Drugs bind to or induce transcription factor proteins that induce transcription of CYP genes–> increased CYP450–> increased metabolism
Significant cross-talk
induce expression of several different families and subfamilies of CYP450 enzymes
Falls into three classes: bile acids, xenobiotics, and fatty acids
Consequences of inhibition or induction
Active drug to Inactive metabolite
Induces: see less effect
Inhibit: increase pharmacologic effect
Inactive drug to Active metabolite
Induce: increase pharmacologic effect
Inhibit: decrease pharmacologic effect
Active drug to Reactive metabolite
Induce: form more increase toxicity
Inhibit: reduce reactive metabolite see less liver injury
Induction of metabolism results from activating transcription factors
increases synthesis of enzyme, sometimes drugs induce the same CYP450 which metabolize the drug itself, this is referred to as autoinduction
