Metabolism Flashcards
Examples of reactive metabolites: Meperidine Morphine Acetaminophen Furosemide Sulfamethoxazole Cyclophosphamide
Meperidine➡️nor-meperidine Morphine➡️morphine-6-glucuronide Acetaminophen➡️benzoquinoneimine Furosemide➡️furo epoxide Sulfamethoxazole➡️nitroso sulfomethoxazole Cyclophosphamide➡️acroleine
Examples of bioactivation (pro-drugs)
Cefuroxime auxetil, Methydopa
ACEi Enalapril Ramipril
Valacyclovir➡️vala triphosphate
Fancyclovir➡️pencyclovir
These are biochemical reactions that are catalyzed by enzymes. And examples.
yes Phase 1 and 2 metabolism
Phase II metabolism examples
Conjugation (ADDITION) metabolism
Glucuronidation, glutathione conjg. sulfonation, acetylation and methylation
Phase 1 metabolism examples
Functional grps: OH, NH2, COOH, SH etc
Oxidation reduction hydroxylation deamination dealkylations demethylation oxidative deamination
Cytochrome oxidations (CYP450), reductase, aminase and monoamine oxidase (MAO)
In phase 1, alcohol oxidations yield what?
1* alc oxidation➡️aldehyde➡️acid 2*➡️ketone 3*➡️no oxidation methanol➡️formaldehyde ➡️formic acid- causes blindness ethanol➡️acetaldehyde Ethylene glycol➡️oxaldehyde➡️oxalic acid
Both mechanisms are to create a polar substrate to be excreted.
Bacteria resident in the GI tract are involved in this reduction reactions.
Oxidation and Reduction.
Azi and Nitro reductions
What drug undegoes Azoreduction?
Azoreduction bond (-N=N-)
Sulfasalazine (in gut)➡️ 5aminosalicylic acid (5ASA) + Sulfpyridine
5ASA - Mesalamine
In Nitro reduction, what group does this produces? Drug examples that undergo this nitro and carbonyl reduction.
= amine (NH2) group
Chloramphenicol and Clonazepam- Nitro red.
Acetohexamide- carbonyl red.
Two functional groups that undergo hydrolysis, also for fixed oils, give catalyzing enzyme and products.
Esters ➡️ by esterases =acid + alcohol
Amide➡️ by amidases= acid + amide
Fixed oils➡️ by ester hydrolysis= glycerol + fatty acids
ASA and Acetaminophen drug metabolisms
ASA and SA- glucuronidation, glycine congjn, hydrolysis (major), hydroxylation
Ace- glutathion and sulphate congjn, glucuronidation and phase 1 metabolism
Drug examples that undergo deamination and hydrolysis
Deam: Amphetamine and Dopamine
Hydrolysis: Valacyclovir➡️Acyclovir
Famcyclovir➡️Pencyclovir
What metabolism adds glucuronic acid, drugs: aceta, morphine, diazepam, sulfathiazole, digoxin and SA.
What catalyzing enzyme?
Glucuronidation by Uridenyl Diphosphate Glucuronyl Transferase (UDP GT)
Ethacrynic acid and acetaminophen (to reduce what toxicity?) undergoes which drug metabolism? By what enzyme?
Glutathione conjg by enzyme Glutathione S-transferase (GST)
-reduced hepatotoxicity
1* amines undergo what metabolism (add acetyl grp NH2, OH) by what enzyme and drug examples.
Sulfonamides, Isoniazid, Clonazepam and Dapsone
by enzyme N-acetyl transferase
The only amino acid conjugation by what enzyme and drug examples
Glycine conj by Acetyl transferase
SA (75% of SA is excreted aft metabolism), Nicotinic acid (Niacin), deoxycholic acid
Sulfate conjugation is by what enzyme and what drug examples.
Sulfotransferase
Acetaminophen, Methyldopa and Estrone
Merhylation is by what enzyme and what drug examples.
N-methyltransferase
E, NE, DOPA and Histamine
Phase 2 metab. is referred to as what?, parent drug or its metabolite with natural contituents.
Conjugation reaction
Glucuronic acid, glutamine, sulfate and glutathione
How nutritional status affects drug metabolism.
Low protein diet
Vit. C def
Vit. E def
Low protein diet- dec. Oxidative
Vit. C def- Dec. Oxidative pathways
Vit. E def- retards dealkylation and hydroxylation
Most common drug metabolizing cytochrome enzyme, also large grp of monooxygenase enzymes resp for toxic hydrocarbons metabolism. Located where?
Give the coenzyme and susbtrate.
CYP450 located in ER, also mitochondria membrane and highly concentrated in liver and small intestine
NADPH- coenzyme
O2- substrate
Most common enzyme that catalyze phase 1 oxidative reactions.
Most common cytochrome SUBTYPE enzyme is?
CYP3A
-CYP3A4
This metabolism is for 1* and 2*
1*- Steroid and bile acid metabolism
2*- drug metabolism
What drugs undergo halogenation?
Halothane, Chloramphenicol
Species differences between Phase 1 and 2 metabolism
1: Quantitative- presence of enzyme inducers and inhibitors
2: Qualitative
Physiological or disease states affecting drug metabolism.
Liver, renal disease, CHF, hypo hyperthyroidism, alteration of albumin production as in elderly
This drug undergoes deamination followed by oxidation and reduction of the ketone formed, N-oxi then N-dealkylation and so on.
Amphetamines
Oxidation and complete removal of substituents at Carbon 5.
N-dealkylation at N1 and N3
So on
Barbiturates
In the side chain N10:
N-dealkylation and N-oxidation then scission
Phenothiazines
Acetylation at N4 amino group
conjg with glucuronic acid:
-or sulfate at N4 amino grp
-or acetylation at N1 amino group
Sulfonamides
Hepatic microsomal enzymes
Extra hepatic microsomal enzymes
Hepatic non-microsomal enzymes
H: Cytochrome IN liver
Extra H: Cyto OUT of the liver
H non: Acetylation, sulfate, GSH, alcohol, dehydrogenase, hydrolysis
What enzyme catalyzes most conjugation reactions?
UDP GT
Most common metabolic reaction in the GI.
Most common phase 1 metabolic reaction.
Most common metabolic reaction in human.
Hydrolysis
Oxidation
Glucuronidation
Most common CYP3A4 inhibitors?
Eryth, Clarith, GFJ, Ketoconazole, Cimetidine, Protease inhibitors
Most common CYP3A4 substrates?
BZD, statins, Digoxin, Sildenafil
Most common CYP2D6 substrate and inhibitor?
Codeine and Fluoxetine
Most common CYP3A4 inducers.
Phenobarbitals, Phenytoin, Carbamazepine, Rifampin, St. John’s Wort
Acetaminophen hepatotoxicity can be reduced by?
Glutathione conjugation
