3study Questions-drug Metabolism

Study Questions- Drug Metabolism 1.

List the Phase I oxidation reactions that occur.

Oxidation Reactions • Aromatic Hydroxylation • Aliphatic Hydroxylation • Dealkylation: O-, N-, S• Deamination • Desulfuration • Dehalogenation 2.

Compare the characteristics of extrahepatic drug metabolism with those of hepatic metabolism (enzyme activity, substrate specificity, regulation).

Extrahepatic drug metabolism compared to the liver is… • Contains less enzyme activity • Greater substrate specificity • Independently regulated • Possibly different metabolites 3.

Describe the components that must be present for cytochrome P450 to metabolize a substrate. • • • • •

4.

Heme protein NADPH P450 reductase Phosphatydyl choline (structure) NADPH (provides e-) Oxygen Indicate the subcellular location of cytochrome P450 and enzymes involved in phase II reactions.

P450 often found on smooth endoplasmic reticulum or when this breaks apart to form microsomes. Phase II enzymes may be located in [smooth] microsomes (A small particle in the cytoplasm of a cell, typically consisting of fragmented endoplasmic reticulum), cytosol, or mitochondrial membrane. Microsomes arising from rough ER tend to dedicate their function to protein synthesis while those arising from smooth ER typically are rich in enzymes. 5.

For CYP2D6, describe what the 2D6 refers to.

2D6 refers to the family, subfamily, and gene, respectively. If there is a P# (ex. CYP2D6P1) it indicates a pseudogene, and is not an actual functional form of P450. 6.

Which CYP isozymes are most important (quantitatively) for drug metabolism and which are most important for xenobiotic (toxins and carcinogens) metabolism.

Drug metabolism – CYP3A4, 3A5, 2D6 Xeonbiotic – CYP1A1, 1B1, 2A, 2B, 2E 7.

What is the importance of a mutation in serum pseudocholinesterase for patients who have been treated with succinylcholine?

The mutated pseudocholinesterase has a decreased activity and leads to a prolonged muscle relaxant effect that may lead to apnea (breathing problems). 8.

For each conjugation reaction, list the enzyme which carries out the reaction, the cofactor which ultimately becomes conjugated to the substrate, and the cellular location of the enzyme.

Type of Conjugation Glucuronidation

Reactant UDP glucuronic acid (glucoruonide) Acetyl-CoA (acetyl group) Glutathione (GSH) (whole molecule)

Enzyme UDP glucuronyltransferase N-acetyltransferase

Location Microsomes

GSH-S-Transferase

Cytosol/Microsomes

Glycine Conjugation (Amino Acid Conjugation)

Glycine (amino acid)

Acyl-CoA glycinetransferase

Mitochondria

Sulfate Conjugation

Phosphoadenosylphosphosulfate (Sulfate) S-adenosyl-methionine (methyl group)

N-Acetylation Glutathione Conjugation

Methylation 9.

Cytosol

Cytosol Sulfotransferase Transmethylases

Cytosol

How do the reactions catalyzed by the microsomal form of glutathione S-transferase differ from those catalyzed by the cytosolic glutathione S-transferase?

Microsomal – prostaglandins/leukotrienes Cytosolic – xenobiotic conjugation 10.

What is the basis for the slow acetylator phenotype compared to the fast acetylator phenotype?

The defect in slow acetylators appears to be caused by the synthesis of fewer enzymes rather than of an abnormal form of it. 11.

How does methylation alter a substrate compared to the other types of conjugates that can be formed?

Methylation actually makes the substrate LESS polar and therefore facilitates its reabsorption. 12. Give two examples of nuclear receptors involved in the induction of cytochrome P450 isozymes. For each, list the ligand that binds to the receptor and the isozyme whose expression is altered. Omeprazole – aryl hydrocarbon receptor – CYP1A1, CYP1A2 induced Rifampin – pregnane X receptor – CYP3A4 induced

13.

List two different drugs which act as inhibitors of cytochrome P450. Describe the mechanism of inhibition for each inhibitor.

(Carbon monoxide may also bind to heme rendering the enzyme inactivated) Erythromycin – metabolite binds to heme  inhibition Chloramphenicol – metabolite binds to P450 protein  inhibition 14.

How can potential toxicity associated with the slow acetylation of isoniazid be prevented?

The toxicity is due to interference with pyridoxine and its activities. If pyridoxine is administered the neural toxicity may be avoided (and will not negatively affect those patients that are not slow acetylators). 15.

Why is it important to understand species differences regarding phase I and phase II pathways in rodents, small animals, and humans?

If these are understood they can be applied to human situations? (I don’t know that answer) 16.

Describe the reactions that result in the production of therapeutically active and toxic metabolites from benzopyrene and cyclophosphamide.

Benzopyrene • Two initial epoxides may form, one leading to an active metabolite (becomes dihydrodiol) and the other that becomes a carcinogen (remains an epoxide) • Two different paths Cyclophosphamide • Cyclophosphamide  Aldophosphamide  Phosphoramide mustard (Therapeutic benefit) + Acroleim (bladder toxicity) • In this case aldophosphamide is metabolized into two pieces, one with toxicity and the other without 17.

Under what circumstances did treatment with terfenadine result in potentially fatal cardiac arrythmias?

When administered with Erythromycin and/or ketoconazole (both P450 inhibitors) terfenadine would build up in the body and possibly cause fatal cardiac arrythmias. (now just given as fexofenadine – active metabolite) 18.

What is the basis for the selective action of parathion as an insecticide?

Humans have an esterase that is able to inactivate the “activated” pesticide while insects do not have this esterase. 19.

Give four examples of how drug action can be altered by pharmacokinetic or pharmacodynamic changes.

Pharmacokinetic • Pre-absorption o Tetracyclines – divalent cations create poorly absorbed complexes

•

•

• •

o Pennicillin/Gentamycin – cannot make contact because PenVK deactivates Gent o Cisplatin binds aluminum – utilize administration sets that do not contain aluminum Absorption o Ketoconazole – soluble at acidic pH o GI Flora affected by broad spec abx (enterohepatic cycling) o Gastric motility (time until peak – what if rapid peak necessary or toxic) Distribution o Plasma protein binding – warfarin displaced by other drugs such as furosemide; resistance in cancer patients (more alpha1-acid protein) o Inhibition of transport of export (PGP) Metabolism o Inhibition or Induction of P450 Excretion o Inhibition of active secretion – ex probenacid competes with PenVK for same transporters resulting in increased half-life of PenVK

Pharmacodynamic • Common Receptor o Pindolol is given when hypotension caused by overdose of BP med (Intrinsic Sympathicomimetic Ability – blocks other drug while exhibiting slight agonistic effect) o Same effect – warfarin and aspirin both thin the blood o Antagonistic effects – warfarin (thinning) and Vit K (clotting) 20.

Compare infants and the elderly with respect to changes in drug absorption, distribution, metabolism and excretion.

Absorption • Infants – low gastric acid/prolonged gastric emptying time • Elderly – decreased splachnic blood flow/changes in GI motility Distribution • Infants – inc body water, dec plasma protein, dec body fat • Elderly – dec body water, dec plasma protein (sometimes), inc body fat Metabolism • Infants – generally low activity • Elderly – dec metabolic capability, dec liver mass, dec hepatic blood flow Excretion • Infants – decreased renal blood flow, dec secretion, [relatively decreased GFR] • Elderly – decreased renal blood flow, dec secretion, dec GFR 21.

Why is the development of tolerance to opioids potentially very dangerous?

Tolerance to the euphoric effect generally builds faster than the respiratory depression tolerance. Suffocation 22.

How do the symptoms associated with withdrawal from drug dependence relate to the therapeutic effects of the drug?

Basically the opposite. Depressant (ethanol-barbituate type) – convulsions, significant mortality if untreated Opiate (narcotic-analgesic) – autonomic hyperactivity Caffeine – headache Cocaine – depression