L5 Drug Metabolism Flashcards
What is the enzymatic catalyzed conversion of a drug or xenobiotic compound to their metabolites?
Metabolism
Drug metabolism primarily converts ___ drugs into more ___ metabolites.
Lipophilic; hydrophilic, polar
Most drugs are ___ and are readily reabsorbed in the ___.
Lipophilic; kidney
What are the two general consequences of drug metabolism?
- Increasing water solubility
2. Increased potential for excretion in urine or bile
What is the major site of drug metabolism and 5 other minor sites?
- Liver
- Intestine
- Skin
- Lung
- Kidney
- Brain
True or false - drug metabolism enzymes are expressed in about half of all cells.
False - they are expressed in essentially all cells
CYP450 and some metabolic enzymes are associated with the ___. Most other metabolic enzymes are present in the ___.
ER; cytoplasm
GI + Hepatic metabolism = ?
First pass Effect
What types of reactions occur in Phase I?
Oxidation, reduction, hydrolysis
What happens to the lipophilic drug in Phase I of metabolism?
Introduction/unmasking of a small function group that converts the drug into a more polar metabolite
What types of reactions occur in Phase II?
Conjugation reactions
What happens to the drug metabolite in Phase II?
Introduction of a large, highly polar endogenous functional group onto the drug metabolite; often occurs via the functional group created by Phase I reactions
What class of enzymes functions in 75% of all Phase I reactions?
CYP450
Where are CYP450 enzymes located?
Bound to the membrane of the ER
Why are CYP450 enzymes called “mixed function”?
The enzyme catalyzes a reaction in which two substrates are oxidized simultaneously (drug and the NADPH cofactor)
The most active enzymes for drug metabolism come from which three sub families?
CYP2C, 2D, and 3A
What are the four requirements for CYP450 reactions?
- Drug substrate
- Molecular oxygen
- NADPH
- NADPH-CYP450 oxidoreductase
True or false - there is one CYP enzyme for every structurally distinct chemical.
False - a single compound can be metabolized by multiple CYP450 enzymes and vice versa
What are the two major reason we need Phase II metabolism?
- Drug metabolite may still be active
2. Drug metabolite may not be sufficiently water soluble to allow for efficient excretion
Which Phase has a faster catalytic rate?
Phase II (slightly)
Where do Phase II reactions occur?
Cytoplasm (except glucuronidation)
What is required for a Phase II reaction?
- Drug substrate with a suitable functional group
- Specific enzyme
- Activated high energy co-factor or co-substrate
What is the most frequent and most important of the Phase II reactions?
Glucuronidation
What are inactive compounds that are metabolized in the body to their active forms?
Prodrugs
The ___ accounts for the excretion of most drugs.
Kidney
In addition to the urine, some drugs and their metabolites are excreted in the ___.
Bile (larger molecular weight with polar and lipophilic groups)
What process can significantly prolong pharmacological effects of drugs and why?
Enterohepatic recirculation; enzymes in the GI tract can hydrolyze drug-conjugates, allowing for reabsorption and re-entry into circulation; this process reduces clearance, extends half-life, and increases plasma exposure
What are the two principle mechanisms by which drugs affect the metabolism of other drugs?
- Induction of CYP450 enzymes (enhances metabolism, decreases drug activity except in the case of a prodrug, increases drug clearance)
- Inhibition of CYP450 enzymes (decreases metabolism, increases drug activity except in the case of a prodrug, decreases drug clearance)
What drugs/xenobiotics are known to induce the expression of CYP450 enzymes?
- Rifampin
- Phenytoin
- Phenobarbital
- Carbamazepine
- St. John’s Wort
How do drugs induce CYP450 enzymes?
They serve as ligands for specific TFs that promote increased transcription of CYP450
How do drugs inhibit CYP450 enzymes?
Bind to drug receptor on CYP450
___ increases the bioavailability of drugs metabolized by CYP3A4 in the Gi tract.
Grapefruit juice
How does grapefruit juice affect metabolism?
Contains compounds that inhibit CYP3A4 activity, which decreases metabolism and increases drug bioavailability, potential therapeutic effect, and potential for adverse effects
What is a major 3A4 inducer?
Rifampin (anti-TB drug)
How does rifampin affect cyclosporin?
Rifampin induces 3A4 expression, increasing metabolism of cyclosporin (immunosuppressant drug), which reduces levels of cyclosporin and increases risk of organ rejection
How does rifampin affect clopidrogel?
Rifampin induces 2C19 expression, increases metabolism of clopidrogel, an anti-platelet prodrug, which increases activation of clopidrogel and increases risk of bleeding
What are two potent 3A4 inhibitors?
Itranaconazole and Ritonavir
How does itranaconazole affect cyclosporin?
Itranaconazole inhibits 3A4 activity, leading to reduced metabolism of cyclosporin, increase in cyclosporin levels and increased risk for nephrotoxicity
How does ritonavir affect lopinavir?
Lopinavir is an anti-HIV inhibitor with extensive first pass effect; ritonavir has the same therapeutic effects but with bad GI effects; a low dose of ritonavir inhibits 3A4, decreases first pass metabolism of lopinavir, boosts its levels and its effects
What are some factors affecting drug metabolism?
- Age
- Pregnancy
- Race and ethnicity
- Diet and environment
- Disease
- Metabolic drug interactions
- Interactions with endogenous compounds
- Genetics
How is Phase I metabolism affected in the elderly?
Decreased (30-40%)
What enzymes increase in pregnancy? What enzymes decrease?
Increase: 2C9, 2D6, 3A4
Decrease: 1A2, 2C19
Chemicals in cigarette smoke, charbroiled food, and cruciferous vegetables all induce ___.
CYP1A2
Chronic alcohol use induces expression of ___.
CYP2E1
