Drug Metabolism and Excretion Flashcards
- Describe the general principles and consequences of drug metabolism.
- In general, lipophilic drugs get metabolized into hydrophilic, less active compounds (via Phase I CYP450 enzymes) and then transformed into highly water-soluble inactive substrates (via Phase II enzymes, especially glucuronidation).
- Drug can be directly excreted, go through PI, PII, or PI and II (sometimes PII can happen first).
- Liver is main metabolism organ, but can also occur via intestine, lung, kidney, skin and placenta.
- Oxidation is most common, catalyzed by CYP450 enzymes and cytosolic enzymes.
- Most of the time, drug metabolism is a detox process that makes inactive compounds.
- Sometimes can make a more active compound (codeine –> morphine).
- Can metabolize an inactive compound to the active ingredient; or metabolize to a toxic compound.
- Describe the general characteristics of Phase I and Phase II reactions as related to:
- qualitative and quantitative role in drug metabolism
- enzymes involved
- genetic polymorphisms
- classifications of reactions.
Qualitative and Quantitative Role in Drug metabolism:
- Phase I unmasks functional groups on drugs (OH, NH2, SH) that make drug more water soluble (and also allowing it to be conjugated in PII). These reactions are generally oxidation, reduction, and hydrolysis.
- Phase II = conjugation = puts on substrate on the functional group to make a very polar, water-soluble conjugate that can be easily excreted.
- Reactions are glucuronidation, acetylation, GSH/glycine/sulfate conjugation.
- Because the enzymes are in limited supply, Phase II reactions are more easily saturable.
Enzymes involved: [CYP450, transferases, etc.]
- Phase I uses CYP450 enzymes (3A4, mostly –> substrates must be lipid soluble), reductases, and esterases-amidases.
- Phase II uses transferases of many sorts (most used is glucuronyl transferase).
Genetic polymorphisms:
–Play a significant role for both phases.
-Main Phase I polymorphism in CYP2D6 (which metabolizes codeine –> morphine; can be tested using an amplichip to see if you’re a UM or PM = determines toxicity or lack of therapeutic effect).
-CYP2C19 is another (metabolizes PPIs). CYP2C9 metabolizes warfarin, which has a narrow therapeutic window to begin with, so your genotype matters.
-In Phase II, there is lots of genetic variation in n-acetyltransferase; affects how you metabolize isoniazid.
Classifications of Reactions:
[ex., O-dealkylation is Phase I oxidation (P450)]
-In phase I, CYP450-dependent oxidations = aromatic and aliphatic hydroxylations, and oxidative dealkylation. -Cyp450-independent oxidations = amine oxidases (MAO) and dehydrogenations (alcohol and aldehyde).
-Esterases hydrolyze esters, and amidases hydrolyze amines.
-Can have azo, nitro, and carbonyl reductions.
-In phase II, can have glucuronidation (produces very water-soluble product; transferred group can be removed by beta-glucuronidase so it can undergo enterohepatic recirculation and possible undergo interactions), N-acetylation (less water soluble), GSH conjugation (heavily involved in detoxification), and sulfate conjugation.
- Describe the general characteristics of Phase I and Phase II reactions as related to:
- inducibility-inhibitibility and potential for DDIs
- general developmental patterns of activity and age-related changes in activity
- relative ease of saturability at high drug substrate levels.
Inducibility-Inhibitibility and potential for DDIs:
-Induction = increase in enzyme activity;
inhibition = decrease in enzyme activity.
-Most induction happens with CYP450 enzymes, but can also happen for UGT.
-Induction –> increased enzyme synthesis and decreased turnover; takes 48-72 hours for effect.
-Results in reduced therapeutic effect (accelerate inactivation reaction too much), increased toxicity.
-Inhibition also happens more with Phase I enzymes, generally by inhibition of enzyme synthesis, competitive inhibition, allosteric inhibition, or destroying the enzyme (covalent interactions with another molecule that stop functionality). Quicker to see. Can also observe increased toxicity or reduction in effect. General developmental patterns of activity and age-related changes in activity.
Perinatally, enzymes aren’t well developed.
Neonatally, there are variable patterns.
In old age, CYP450 enzymes decrease (in 1/3 the aging population).
-Relative ease of saturability at high drug substrate levels
-Phase I enzymes not easily saturated, but Phase II enzymes can be if drug dose is too high.
- Explain the therapeutic consequences of induction and inhibition of metabolism. List the clinically relevant inhibitors and inducers on page 8 of the drug metabolism notes.
See above. Therapeutic Consequences of Induction: -Pharmacokinetic tolerance -increased clearance causing reduced therapeutic effect -or increased toxicity.
Therapeutic consequences of inhibition:
- (Phase I more prone) inhibition of metabolism if sufficient hepatic concentration is reached.
- Can also cause decreased clearance and increased toxicity.
-Disease states (hepatic diseases or too much alcohol; generally a reduction in metabolism), genetic factors, sex, diet, individual/ethnic differences can all effect induction/inhibition as well.
P-glycoproteins (from the ABC family on the MDR1 gene) decrease absorption and enhance elimination. Move molecules out of the cells at sites of entry into body and decrease absorption, and enhance elimination at sites of exit. Susceptible to polymorphic variation and drug interactions.
- Describe the general characteristics of drug excretion by the kidney (filtration, secretion, reabsorption and the influence of pH and protein-binding on these processes).
- Renal clearance is the major form of clearance, especially for water-soluble and non-volatile compounds.
- Units = mL/min. Glomerular filtration occurs at rate of 120 for smaller drugs, and only free drug.
- Active secretion (from blood into urine) can happen faster, at a rate of 120-600.
- Occurs with stronger acids/bases, and drugs that have been ionized (or otherwise changed by metabolism).
- Drugs not changed by metabolism (uncharged, lipid-soluble) cleared MUCH slower because they keep getting reabsorbed in the tubules via passive diffusion. -Can use trapping to change urinary pH and trap compounds (diffusion of weak acids/bases dependent upon urine ph).
- Protein-bound drugs can’t really be filtered.
- Tubular secretion is the slowest (for lipid-soluble, uncharged compounds that get cleared at rate of urine formation = 1 ml/min if you don’t have PI/PII).
- Describe the therapeutic implications of enterohepatic recirculation of drugs.
- Many drugs excreted in bile to be excreted in feces or urine, generally because they’ve had some conjugate group attached to them.
- However, when they’re secreted into the bile, the conjugate group can be hydrolyzed off (like beta-glucuronidase) and reabsorbed by gut via enterohepatic recycling.
- This reduces elimination and prolongs half-life, creating a reservoir of recirculating drug (generally for MW > 300).
- Antibiotics can reduce bacterial enzymes in gut and decrease enterohepatic recycling and decrease plasma drug levels (potentially a mech for DDIs).
- Describe the factors influencing drug passage from plasma to breast milk.
- Many drugs cross into breast milk, but generally at levels low enough that they never have a therapeutic effect.
- Milk is more acidic and has a tendency to trap basic compounds.
- Lipid soluble compounds also find their way into breast milk, but not drugs with high levels of protein binding.
- Drugs with rapid clearance generally cleared too quickly to ever get into milk.
- Drugs can also affect milk synthesis and secretion by affecting certain hormones.
