PHARM: Drug Metabolism Flashcards
What are the common characteristics of drug metabolizing enzymes?
Causes a chemical change in drug; forms more water-soluble metabolite; make metabolite more acidic ; terminates the drugs action
Where can cytochrome P450 be found in the body?
Highly concentrated on the ER of hepatocytes in the liver, but also in the SI, lungs, kidney, skin
What other enzyme is necessary for cyP450’s action? What is the other’s function w/ reference to cyP450?
NADPH Cytochrome P450 reductase; It transfers lectrons to P450
What is the general reaction performed by cytochrome P450?
Molecular oxygen (O2) is split; one atom of oxygen forms water and the other is added to the substrate as a hydroxyl group
How are cyP450s named?
CYP #(family) Letter(subfamily) 2nd # (individual)
What are the general classes of drug metabolizing reactions?
Non-synthetic Phase I and Synthetic Phase II
What class of drug metabolizing reaction is catalyzed by CYP450?
Phase I Non-Synthetic Oxidation Reactions
What is the major class of substrates metabolized by CYP1A?
Polycyclic hydrocarbons (naphthalene, benzopyrene)
What induces the expression of CYP1A?
Polycyclic hydrocarbons (found in cigarette smoke)
What are the major differences between CYP1A1 and A2?
A1 is only extrahepatic and is inducible by Aryl hydrocarbon receptor and A2 is constituitively and exclusively expressed in the liver but it is also inducible by exposure to broccoli, cauliflower, cigarette smoke and caffeine
What are the risks and potential consequences associated with CYP1A polymorphisms?
If people with hyper-active polymorphisms and are exposed to a lot of cigarette smoke they have a higher chance of developing lung cancer
What is metabolized by CYP1B1?
Polycyclic hydrocarbons, steroids, retinoic acid, arachidonic acid
What condition is caused by mutational deficiency in CYP1B1?
Primary Congenital Glaucoma
What are the primary forms of CYP2A in humans?
CYP2A6 and CYP2A13
What is metabolized by CYP2A6 and what are the consequences associated with polymorphisms in the enzyme? What can induce its expression?
Nicotine– implications for nicotine dependence- those who can’t metabolize nicotine as well suffer more from bad side effects when smoking; can be induced by phenobarbital and rifampicin
What is metabolized by CYP2A13 and where is it expressed?
Metabolizes nitrosamine, NNK, and is expressed in the resp. tract
What is the major form of CYP2B in humans?
2B6
What are the substrates of CYP2B6? What can its expression be induced by?
Metabolies MDMA, and are only metabolizers of polybrominated diphenyl ethers (flame retardants); inducible by phenobarbital, rifampicin, and phenytoin through constitutive active receptor
What is metabolized by CYP2C?
about 30% of commonly used drugs including omeprazole (Prilosec), Diazepam (Valium), and Clopidogrel (Plavix)
What is metabolized by CYP2D6?
Oral opiates (codeine, dextromethorphan, hydrocodone, oxycodone)
What is the drug interaction between Prozac and tamoxifen?
Tamoxifen is metabolized into its active form by CYP2D6 which is inhibited by some SSRIs, decreasing the effectiveness of tamoxifen
What is metabolized by CYP2E1?
EtOH and small hydrocarbons (benzene, toluene)
What CYP450 is inducible by ethanol?
CYP2E1
What is the mechanism of acetaminophen toxicity after taking acetaminophen with alcohol
Ethanol induces the upregulation of CYP2E1 expression causing more acetaminophen to be metabolized into harmful metabolite NAPQI
What CYP450 metabolizes over 50% of commonly used drugs?
CYP3A4
Which CYP450 is inducible by pregnane X receptor?
CYP3A4
What are common inhibitors of CYP3A4? Inducers?
Cimetidine and Grapefruit juice (bergamottin); Rifampicin and phenobarbital
What is the primary form of flavin monooxygenase in the adult? Primary form in the fetus?
FMO3; FMO1
What type of reaction is catalyzed by flavin monooxygenases?
N- and S- oxidation phase I reactions
What is trimethylaminuria and what is its basis?
Rare metabolic disorder due to polymorphism in FMO3, which metabolizes trimethylamines from breakdown of fish and meat, and so the individuals usually have a fishy odor
What reaction is catalyzed by alcohol dehydrogenase and what is the subsequent reaction and enzyme?
Ethanol is converted to acetaldehyde by alcohol dehydrogenase and then to acetic acid by aldehyde dehydrogenase
What are the three major types of reduction reactions?
Azoreduction, nitroreduction, ketoreduction
What are the types of hydrolysis reactions that occur in phase I drug metabolism
Esterase rxns, amidase rxns, and epoxide hydrolase rxns
What are the major 6 types of phase II conjugation rxns?
Glucuronidation, Sulfate conjugation, acetylation, glutathione conjugation, methylation, glycine conjugation
True or False: A simple hydrocarbon cannot be conjugated; it must undergo a phase I reaction first.
True
What are the main general functions of phase II conjugation reactions?
To make molecules more acidic and more water soluble
Which type of phase II conjugation reaction is quantitatively the most common reaction?
Glucuronidation
What enzymes catalyze glucuronidation reactions?
UDP-glucuronyltransferases
Drug molecules must have at least one of which functional groups to undergo glucuronidation?
Hydroxyl, carboxyl, amine, or sulfhydryl
What happens to a compound following glucurondiation?
It can be actively secreted into bile
What is enterohepatic cycling?
The process by which molecules (esp. amines, sulfhydryls) that are labile to acid or microbiota enzymes can be metabolized back into the parent drug and reabsorbed into circulation
What developmentally induced enzyme is responsible for bilirubin conjugation/metabolism
UGT1A1
Why are premature infants in danger of developing kernicterus?
Bilirubin is metabolism by UDP-glucuronosyltransferase 1A1 enzyme which is developmentally induced. Premature infants do not express adequate levels of this enzyme and so bilirubin can acculumate and cause kernicterus in the brain without intervention
What is kernicterus?
When bilirubin concentrations are high it can cross the BBB and cause CNS damage and ultimately death
What is Gray baby syndrome?
Occurs in infants given the antibiotic chloramphenicol, which requires a conjugation reaction catalyzed by UGT1A1 to clear. The build-up of the drug causes CNS damage, a gray appearance, and death
Crigler-Najjar syndrome: What is it?
A genetic disorder where an individual has a deficiency in UGT1A1– typically fatal early in life
Why is it necessary for UGT2B4 to be expressed in fetuses?
Bile acids cannot cross the placenta and so the fetus must be able to metabolize their own, as well as some of mom’s, bile acids
What enzymes catalyze sulfate conjugation reactions?
Sulfotransferases
What makes sulfate conjugation reactions saturable?
Sulfotransferases require PAPS, which is limited in the cell
What functional group undergoes acetylation reactions? What enzyme catalyzes these reactions?
Primary amines; N-acetyltransferase
What acetylation disorders are associated with slow acetylators? Rapid acetylators?
Isoniazid-induced neurotoxicity, Hydrolyzine-induced lupus, arylamine-induced bladder cancer; Isoniazid-induced hepatitis
What enzymes catalyze glutathione conjugation reactions? What product is formed?
Glutathione-S-transferases; mercapturic acids
Which conjugation reaction happens to reactive chemicals like eoxides, arylamines, and phenols?
Glutathione conjugation
What is associated with GSTM1 null mutations?
Cancer
What type of phase II conjugation reaction makes compounds more lipid-soluble?
Methylation reactions
True or False: Amino acid conjugation reactions can be saturated.
True
