Drug Metabolism & Elimination Flashcards
Describe the general principles and consequences of drug metabolism.
Drug metabolism is also known as biotransformation. Drug metabolizing enzymes have endogenous substrates and play a role in normal metabolism (duh). The liver is the primary metabolism organ but the intestines [6%], lungs [30%], kidneys [8%], skin [1%], placenta [5%], and bacteria in the lumen of the intestines all play a role in metabolism. Oxidation is the most frequent metabolism pathway. Oxidation and other transformations are catalyzed by membrane bound proteins in the SER and soluble enzymes in the cytosol. Finally, lipid soluble compounds are converted to more water soluble compounds for easy excretion.
What are the general characteristics of Phase I reactions?
Phase I reactions usually insert or unmask a functional group on the drug [OH-, -NH2, -SH] that renders the molecule more water-soluble and the molecule can then undergo conjugation in a Phase II reaction. Phase I reactions include: Oxidation, reduction, hydrolysis.
What are the general characteristics of Phase II reactions?
Phase II metabolism involves attaching larger endogenous biochemical units (not just oxygen) to the drug by way of cofactor enzymes. Makes a highly water soluble conjugate that is readily excreted in the urine. This process is referred to as conjugation. Reactions include glucouronidation, acetylation, and some glucothione and sulfate conjugation. Sometimes Phase 2 reactions can preceed Phase 1 reactions.
Describe how Phase 1 and Phase 2 reactions relate to qualitative and quantitative role in drug metabolism.
CYP3A4 is responsible for 50% of drug metabolism, and CYP1, 2, 3 are also of primary importance in drug metabolism. Therefore, Phase I reactions are responsible for more drug metabolism than Phase II.
Which enzymes are involved in Phase I and Phase II reactions?
Phase 1 uses: oxidizers (microsomal CYP450 and non-microsomal CYP450), reducers, and hydrolyzers (esterases, amidases)Phase 2 uses: transferases
How are genetic polymorphisms important in Phase I and Phase II reactions?
There’s extensive genetic variability of CYP enzymes (phase I). There’s extensive genetic variability of N-acetylation enzymes (phase II). This can be important in terms of analgesic response (CYP2D6 for codeine to morphine) and blood clotting with regard to Warfarin.
What reactions are CYP450 dependent?
Aromatic hydroxylations, aliphatic hydroxylations, epoxidation, oxidative dealkylation, o- and s-dealkylation, n-oxidation, secondary and tertiary amines, s-oxidation, deamination, desulfuration, dechlorination.
How is age related to the effects of Phase I and phase II reactions?
Perinatal: some enzymes may not be fully developedNeonatal:can usually metabolize at lower rates than adultsOld age: 1/3 decrease in CYP activityNot much change in Phase II activity with aging.
Please discuss Phase I and Phase II reactions in regard to inducibility.
Phase I reactions can be induced or inhibited with relative ease. Phase 2 are not usually inducible. Phase 2 glucourinidations are inducible but not to the extent that Phase I reactions are, especially CYP450).
Please discuss Phase I and Phase II reactions in regard to developmental patterns of activity.
Some Phase II enzymes only show up at a certain age– infants often lack the metabolizing enzymes that adults have (eg. glucuronidation enzymes). Also, depending on in what state your liver is in, it can be better or worse at both phases of metabolism. Some phase 1 enzymes occur at higher rates in pediatric patients, so it is important to be aware of theses types of situations.
Please discuss Phase I and Phase II reactions with regards to relative ease of saturability at high drug substrate levels.
Phase II reactions usually saturate faster than Phase I reactions.
What is induction?Explain the therapeutic consequences of induction.
Increased drug metabolism activity in response to certain compounds including drugs.Maximal effects of enzyme induction usually seen in 7-10 days and require similar time to dissipate.Production of pharmacokinetic tolerance: induction by a drug of its own metabolism, e.g., phenobarbital, meprobamate, carbamazepine.Induction by one agent may increase the clearance of other drugs. The resulting drug interactions may have clinical implications such as reduced therapeutic effect of drug whose elimination is accelerated or increased toxicity via a toxic metabolite.One drug may induce the metabolism of another to toxic metabolites; e.g., ethanol induces CYP2E1 that metabolizes acetaminophen to a hepatotoxic metabolite.Very important for CYP450, not very important in Phase II reactions.
What is inhibition? Explain the therapeutic consequences of inhibition?
Inhibition is decrease in drug metabolizing activity by certain compounds.Inhibition of metabolism can occur as soon as sufficient hepatic concentration is reached (generally within hours), although time to effect on steady state plasma concentration dependent on the inhibited drug’s half-life.Inhibition by one agent of the metabolism of another can result in decreased clearance of the inhibited drug, higher circulating plasma levels, and increased toxicity.Very important for CYP450, not very important in Phase II reactions.
Describe the therapeutic implications of enterohepatic recirculation of drugs.
Drugs and drug metabolites with molecular weights higher than 300 may be excreted via the bile, stored in the gallbladder, delivered to the intestines by the bile duct, and then reabsorbed into the circulation where it can return to the liver by way of the superior mesenteric and portal veins. This process reduces the elimination of drug and prolongs its half-life and duration of action in the body. For some drugs (e.g., morphine and ethinyl estradiol), this effect creates a “reservoir” of recirculating drug that can amount to about 20% of total drug present in the body.
Describe the factors influencing drug passage from plasma to breast milk.
Select drug(s) with clinically insignificant amounts of passage into breast milk. The milk concentrations of ethanol and lithium can approximate maternal plasma levels.Drugs with rapid clearance (> 0.3 L/hr/kg) and no active metabolites are generally cleared too rapidly by the mother to affect the nursing infant.Milk is more acidic than plasma (pH 6.5 vs pH 7.4) therefore tendency to accumulate basic compounds (e.g., opiate analgesics) by ion-trapping.Lipid soluble compounds → generally increased milk concentration.High protein binding → decreased milk concentration.Drugs contraindicated by American Academy of Pediatrics: amphetamines, cocaine, bromocriptine, ergotamine, lithium, nicotine, most antineoplastic agents, drugs of abuse.Drugs that can affect milk synthesis, secretion, and / or ejection through effects on prolactin (PRL) and / or oxytocin release include: dopamine receptor agonists (↓ PRL release) and antagonists (↑ PRL release) and ethanol (↓ oxytocin release).
