Drug Metabolism Flashcards
True or false: lipophilic compounds are efficiently eliminated from the body.
False; this is why lipophilic compounds can accumulate in adipose tissue and membranes, and why they are poorly excreted in the urine.
True or false: most drugs are lipophilic and readily reabsorbed in the kidney.
True! Unbound drug molecules are filtered through the glomerulus and readily reabsorbed in the kidney tubules under the influence of pH and urine flow rate.
Why does the fact that most drugs are lipophilic contribute to drug accumulation and toxicity in the body?
Lipid-soluble drugs are readily reabsorbed in the kidney tubules, causing a higher concentration in the systemic circulation and resulting drug accumulation/toxicity.
What is drug metabolism?
the enzymatically catalyzed conversion of a drug or xenobiotic compound to its metabolites
What are the primary roles of drug metabolism?
- to inactive and detoxify pharmacologically active drugs and xenobiotics
- to enhance drug excretion/elimination
What is the one situation in which drug metabolism activates drug compounds instead of inactivating them?
when prodrugs are administered
What are examples of prodrugs discussed in class?
Irinotecan –> SN-38
others include clopidrogel, codeine, prednisone, levodopa, and captopril
What is the major site of drug metabolism? Which organ plays a secondary role?
- liver=main site
- intestine also plays a significant role
True or false: drug metabolism enzymes are only expressed in certain cells, like hepatocytes.
False- drug metabolism enzymes are expressed in essentially ALL cells.
What are the major subcellular sites of drug metabolism?
- ER (CYP450 and others, like glucuronosyltransferase)
- cytoplasm (most other metabolic enzymes)
When does a drug have 100% bioavailability?
when it is injected intravenously
Provide an example of a drug-conjugate that is NOT inactive.
morphine (when it undergoes phase II reactions, it is not inactivated, but converted to the more active morphine-6G form)
Besides the liver and intestine, where can drugs be metabolized?
skin, kidney, lungs, brain
What are the major enzymes involved with Phase I rxns?
cytochrome P450 enzymes (CYP450)
- specifically catalyze oxidation rxns
- account for 75% of all phase I rxns
CYP450 rxns require:
- drug substrate
- molecular oxygen
- NADPH
- NADPH-CYP450 oxidoreductase
Which CYP enzyme represents 30% of all CYP450 enzymes in the liver and accounts for the metabolism of >50% of clinically used drugs?
CYP3A4
CYP450 superfamily enzymes are expressed at highest levels where in the body?
liver and GI tract
Most active enzymes for drug metabolism are which subfamilies?
CYP2C, CYP2D, and CYP3A
Subcellularly, where do most phase II rxns occur? What is the exception?
cytoplasm- exception is glucuronidation, which occurs on ER membrane
Which drugs are direct targets for phase II metabolism because they already contain small polar functional groups?
morphine and isoniazid
What is the most frequent and important of all phase II rxns? What is this rxn catalyzed by?
glucuronidation, catalyzed by UDP-glucuronosyltransferase (UGT)
When/why are prodrugs given?
when the prodrug has a better pharmacokinetic profile than its active metabolite (solubility, absorption, distribution, stability, toxicity, etc.)
Which organ accounts for the excretion of MOST drugs?
kidney
What happens to drugs that are recirculated via enterohepatic circulation?
these drugs are actively transported into the bile and stored in the gallbladder before release into GI tract (and ultimately excreted in feces); enterohepatic recirculation can significantly prolong the pharmacological effect of drugs
How does grapefruit juice affect metabolism of certain drugs?
Grapefruit juices increases oral bioavailability of CYP-3A4-metabolized drugs (compounds in grapefruit juice inhibit CYP3A4 activity, thereby decreasing 3A4 metabolism of drug in the GI tract–> more drug reaches liver and systemic circ–> potential for increased therapeutic effect–> also potential for adverse effects)
How does CYP3A4 affect drug bioavailability?
It is expressed in the GI tract and metabolizes drugs during the absorption processes, thus decreasing F (part of first pass effect)
Why is a dose reduction necessary in the elderly?
due to decreased activity of phase I enzymes/metabolism
What is pharmacokinetic tolerance? Provide an example of a drug that displays this.
It describes the phenomenon by which some drugs induce the enzyme responsible for their own metabolism, reducing levels of active drug over time.
*Ex: carbamazepine
What are the major features of phase I vs. phase II metabolic drug reactions?
- phase I: oxidation, reduction, hydrolysis
- phase II: conjugation
What are the 2 principal mechanisms underlying metabolic drug-drug interactions?
- induction of metabolic enzymes
- inhibition of metabolic enzymes
What are some well-known inhibitors of CYP450 isozymes?
ritonavir, grapefruit juice, fluconazole, ketoconazole, itranaconazole, omeprazole, erythromycin, clarithromycin
What are some well-known inducers of CYP450 isozymes?
St. John’s wort, rifampin, glucocorticoids, carbamazepine, phenobarbital, phenytoin, pioglitazone
(St. John Rides in a Green Car to the Party, Pool, and Picnic)
How do rifampin and ritonavir differentially affect cyclosporin metabolism?
- rifampin: 3A4 inducer; increases metabolism of cyclosporin, thereby increasing risk of organ rejection
- ritonavir: 3A4 inhibitor; decreases metabolism of cyclosporin, thereby increasing risk for nephrotoxicity
What are the principal factors known to influence drug metabolism?
- age
- pregnancy
- diet and envt.
- disease
- metabolic drug interactions
- interactions b/t drugs and endogenous compounds
- genetics
What leads to gray baby syndrome?
Infants inherently have a deficiency in conjugating phase II enzymes. When they are given chloramphenicol (used for treatment of bacterial infections), they get a buildup of a phase I metabolite, resulting in circulatory collapse and cyanosis.
How do inflammatory cytokines affect CYP450 isoforms?
decrease expression of many isoforms
How does cigarette smoke affect drug metabolism?
Chemicals in cigarette smoke induce CYP1A2 3-fold, which may cause smokers to require higher doses of drugs metabolized by CYP1A2.
