| How does the body metabolize drugs? | It involves the same pathways and transport systems that are utilized for normal metabolism of dietary constituents.
They are considered as xenobiotics, which has made it difficult to produce them because of interindividual variations, drug-drug interactions and species differences (in trials) |
| What is the form of drugs that we are able to eliminate? | Hydrophobic drugs are hard to eliminate as they accumulate in fat, so xenobiotic-metabolizing enzymes convert them into hydrophilic ones to be eliminated via urine (decreasing biological activity of the drug) |
| What are the toxic effects of drug-metabolizing enzymes? | They may metabolize drugs into toxic or teratogenic metabolites, when this unstable metabolite reacts with cells, may be electrophilic or nucleophilic
E.g: Epoxidation microsomal reaction are carcinogens inducing cellular and tissue necrosis |
| What is drug biotransformation? | They are reactions done to enhance the hydrophilicity of drugs to make them susceptible to be excreted renal.
two rxn: oxidation-reduction/ hydrolysis (phase I), and Conjugation (phase II)
They can either convert drug into inactive form, or convert it into a toxic form, or convert prodrug into active form |
| Where are the sites of drug metabolism? | Kidneys, GI (oral drugs), lungs, skin.
However liver is the most important undergoing the first-pass effect
So we give higher dose oral than IV |
| What is the phase I drug reaction? | Polar reactive group added to the drug to make it suitable for phase II, microsomal microoxidation, cytosolic or mitochondrial oxidation, reduction and hydrolyses |
| What is the phase II drug reaction? | Products of phase I undergo conjugation with another functional group (hydroxyl, halogen, methyl, carboxyl)
Modify compounds by attaching hydrophilic groups to create more polar conjugate, less toxicity and more readily excreted. |
| What is drug-drug interaction? | Effect of phase I or II reaction also depends on presence of other drugs, barbiturates for example are powerful enzyme inducers while others (like cimetidine) are able to inhibit these enzymes thus less metabolization. |
| What are prodrugs? | Drugs administered in inactive form that need metabolization to be active, used to facilitate the elimination half-life of a drug
E.g: Perfalgan (paracetamol injectable) proparacetamol formed by esterification of paracetamol and carboxylic acid diethylglycine making it more water-soluble, fast hydrolysis by plasmatic esterase. |
| Give some examples of prodrugs? | Irinotecan (prodrug of SN-38 chemotherapy)
Prednisone (prodrug of corticosteroid, anti-inflammatory) |
| What are phase I oxidation reactions? | They involve enzymes on SER of hepatocytes or other cells, oxidases catalyze these reactions (typically cytochrome p450 heme monooxygenases, AKA CYP), which are microsomal oxidases involved in metabolism of 75% of drugs |
| How is the CYP reaction? | CYP uses O2 on drugs + NADPH + H+ to oxidize the drug by adding OH to it
Most of the CYPs in liver exhibit broad substrate specificity (superfamily) , which is divided into subfamilies and enzyme families and gene number (so they are called CYP4A3 for example) |
| What are the CYPs found in humans? | 12 CYPs (CYP1A1,1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, and 3A5) are the ones involved in oxidation of xenobiotics, seen in the liver, some in GI, lungs, kidneys, and CNS.
Most active ones are CYP2C, 2D and 3A
CYP3A4 is most abundant and used in metabolism of 50% of used drugs.
other subfamilies are not involved in drug metabolism but in activation of protoxins and procarcinogens (CYP1A, CYP1B, CYP2A, CYP2B, and CYP2E ). |
| What are some of the CYP-dependent oxidation reactions? | Alipathic Hydroxylation (barbiturates, digotoxin, cyclosporin)
Aromatic hydroxylation (propranolol, phenytoin)
N-Dealkylation (lidocaine)
O-Dealkylation (Codeine)
S-oxidation (Cimetidine)
N-Oxidation (Quinidine)
Desulfuration (thiopental)
Epoxide formation (carbamezipine) |
| Describe the metabolism of paracetamol. | It is absorbed into blood as acetaminophen, where 85 % of it are directly conjugated and excreted.
The remaining 15% is oxidized by CYP and natural product solvents into NAPQI (N-acetyl parahydroquinoneimine), which may either bind to proteins and have a toxic effect, or be conjugated by GSH and be excreted. |
| How is the drug-drug interaction on CYPs? | More than 95% of drug biotransformations are done by CYP, so when 2 drugs coadmin and metabolized by same CYP they will compete, which can result in the inhibition of metabolism of one or both drugs leading to elevated plasma levels.
So if there is a narrow therapeutic index for the drugs they will exhibit toxicity. |
| Give some inducers and inhibitors of CYP. | Inducers (Tabac, cortisol, Rifampicine)
Inhibitors (griffon juice) |
| What is the effect of cyclosporins A on CYP? | Cyclosporin is an immunosupressant used widely in drug transplantation.
as they inhibit CYP3A4, in addition to the inhibition of T cells. |
| What are other pathways used to oxidize lipophilic molecules other than CYP? | Alcohol dehydrogenase (ADH) is an enzyme found in microsomes that oxidize alcohols in aldehydes, which is the basis of intoxication due to ethanol consuption.
RK: Ethanol has a higher affinity on ADH than methanol so it can be used as a treatment of methanol toxicity.
Ethanol is converted into acetaldehyde by MEOS (microsomal ethanol oxidizing system), which is then further oxidized by ALDH (aldehyde dehydrogenase) into acetate in mitochondria which is eliminated in the circulation. |
| What is the mechanism of alcohol flush reaction? | It is due to inherited deficiency in ALDH, causing increased acetaldehyde and thus flushing syndrome (characteristic of Asian population where we see erythema of face, neck, shoulders and maybe the entire body) |
| What is the consequence of methanol toxicity? | Methanol is converted into formaldehyde which damages tissues, including optic nerve and may cause blindness, or other CNS tissues causing coma/ respiratory death.
Its antidote is fomepizole which inhibits ADH |
| What is the monoamine oxidase enzyme? | Mitochondrial non-CYP oxidase, oxidizes amine containing products like catecholamines, xenobiotics, drugs.
AKA MAO enzyme, acts on epi, NE, serotonin (MAO-A) and phenylalanine (MAO-B) and converts them into an aldehyde + ammonia. |
| What is the role of dopa-decarboxylase? | Conversion of L-dopa into dopamine (active form) |
| Describe the metabolism of norepinephrine? | COMT (cateco-O-methyl transferase) will convert NE into normetanephrine, which is then acted on by MAO into normetanephrin aldehyde (or directly norepi by MAO then COMT makes it metan).
Then ALDH converts them into VAM acid/ dihydroxyVAM.... |
| List some CYP-independent oxidation reactions. | ALD/ALDH (ethanol and pyridoxine)
Oxidative Deamination (histamine and NE)
Decarboxylation (Levodopa) |
| What are reduction reactions? | Nitro, Diazo, Carbonyl... are susceptible to reduction. |
| What is nitroreduction? | aromatic amines undergo reduction by bacterial and mammalian nitroreductase system
Azoreductase is similar to nitro.
EX: nitrobenzene reduction into aniline. |
| What is disulfide reduction? | disulfiram (Alcohol anatgonist blocking ALDH) reduced into sulfhydryl constituent |
| What is DDT dehydrocholrinase (dehalogenation)? | DDT-dehydrochlorinase is an insecticide, catalizes dehydrochlorination of DDT to DDE Dichlorodiphenyl Dichlorethylene |
| What are hydrolysis conjugation reactions? | hydrolyze or conjugate drugs into larger molecules in order to inactivate it and enhance its excretion and solubility in urine or bile.
It may sometimes activate a prodrug.
Mostly addition of glucuronate, sulfate, glutathione, acetate. |
| What is epoxide hydrolase? | there are two forms (soluble (cytosolic- sEH) and microsomal (mEH)).
Epoxides are highly reactive and can bind to cellular nucleic acids and be carcinogenic, so epoxide hydrolases deactivate the toxic compounds produced by CYP.
Ex: Benzopyrene transformed into epoxides |
| What is carboxylesterase? | Superfamily of enzymes catalyzing hydrolysis of ester and amide containing chemicals.
They catalyze activation of prodrugs (like irinotecan into SN-38 for chemo) |
| Give an example of hydrolysis of amides with carboxylesterase. | Phenacetin (which is an acetaminophen prodrug) can be deacetylated by carboxylesterase into p-Phenetidine |
| Give an example of hydrolysis of esters? | Esterase hydrolyzing aspirin into salicylic acid (main active metabolite of aspirin.
Another example is enalapril esterase action into enalaprilate. |
