Chapter 4: Drug metabolism

tobacco smoke, carbamazepine, lansoprazole, omeprazole, phenobarbital, rifampin

1A2 inducers?

Carbamazepine, phenobarbital, phenytoin, rifampin

2C19 inducers?

barbiturates, phenobarbital, phenytoin, primidone, rifampin

2C9 inducers?

ethanol, isoniazid

2E1 inducers?

barbiturates, carbamazepine, corticosteroids, efavirenz, phenytoin, rifampin, pioglitazone, st johns wort

3A4 inducers?

induction and inhibition of drug metabolism

A large number of drugs alter their own metabolism and the metabolism of other drugs either by inducing the synthesis of larger amounts of the metabolizing enzymes (usually p450 enzymes in the liver) or by inhibiting those enzymes. Some drugs both inhibit (acutely) and induce (with chronic administration) drug metabolism

glucuronidation

Acetaminophen, diazepam, digoxin, morphine, sulfamethiazole

P-glycoprotein, mdr-1

An ATP-dependent transport molecule found in many epithelial and cancer cells. The transporter expels drug molecules from the cytoplasm into the extracellular space. In epithelial cells, expulsion is via the external or luminal face

CYP isozymes

Cytochrome P450 enzyme species that are responsible for much of drug metabolism

glycine conjugation

Deoxycholic acid, nicotinic acid (niacin), salicylic acid

toxic metabolism

Some substances are metabolized to toxic molecules by drug metabolizing enzymes. Important examples include methyl alcohol, ethylene glycol, and at high doses or in the presence of liver disease, acetaminophen

drug metabolism vs drug elimination

Termination of a drug action requires either removal of the drug from the body (excretion) or modification of the drug molecule (metabolism) so that it no longer has an effect Both methods constitute drug elimination, and both are very important in the clinical use of drugs Almost all drugs (or their metabolites) are eventually excreted, but for many, excretion occurs only some time after they have been metabolized to inactive products

p-gp

____ and other MDR members are also found in the blood-brain barrier and in drug-resistant cancer cells

mibefradil

a calcium channel blocker that is no longer on the market

3A4 inhibitors

amiodarone azole antifungals cimetidine clarithromycin cyclosporine diltiazem erythromycin fluoroquinolones grapefruit juice HIV protease inhibitors metronidazole quinine SSRIs tacrolimus

2D6 inhibitors

amiodarone bupropion cimetidine quinidine SSRIs

2C9 inhibitors

amiodarone chloramphenicol cimetidine fluconazole isoniazid metronidazole SSRIs zafirlukast

deamination

amphetamine diazepam

hydroxylation

amphetamines barbiturates ibuprofen phenytoin propranolol warfarin

3A4 metabolizes

antiarrhythmics antidepressants azole antifungals benzodiazepines calcium channel blockers cyclosporine delavirdine doxorubicin efavirenz erythromycin estrogens HIV protease inhibitors nefazodone paclitaxel proton pump inhibitors STATINS rifabutin rifampin sildenafil SSRIs tamoxifen trazodone vinca alkaloids

2D6 inhibitor inhibits

antiarrhythmics antidepressants beta blockers clozapine flecainide lidocaine mexiletine opioids

1A2 inhibitor inhibits

apap caffeine clozapine haloperidol tamoxifen theophylline TCA warfarin

1A2 metabolizes

apap caffeine clozapine haloperidol tamoxifen theophylline TCA depressants warfarin

2E1 metabolizes

apap enflurane ethanol halothane

n-oxidation

apap nicotine

sulfation

apap, methyldopa

esters

aspirin clofibrate procaine succinylcholine

2C9 inhibitor inhibits

barbiturates celecoxib chloramphenicol doxorubicin ibuprofen phenytoin chlorpromazine steroids tolbutamide warfarin

2C9 metabolizes

barbiturates celecoxib chloramphenicol doxorubicin ibuprofen phenytoin chlorpromazine steroids tolbutamide warfarin

pharmacogenomics

because recent advances in genomic techniques are making it possible to screen for a huge variety of polymorphisms, it is expected that _________ will become an important part of patient evaluation in the near future, influencing both drug choice and drug dosing.

activate

biotransformation serves to ________ prodrugs.

N-dealkylation

caffeine morphine theophylline

dehydrogenation

chloral hydrate ethanol

reduction

chloramphenicol clonazepam dantrolene naloxone

s-oxidation

chlorpromazine cimetidine thioridazine

1A2 inhibitors

cimetidine fluoroquinolones grapefruit juice macrolides isoniazid zileuton

acetylation

clonazepam, dapsone, isoniazid, mescaline, sulfonamides

O-dealkylation

codeine

2C19 metabolizes

diazepam naproxen omeprazole phenytoin propranolol topiramate TCA warfarin

2C19 inhibitor inhibits

diazepam phenytoin topiramate

methylation

dopamine, epinephrine, histamine, norepinephrine, thiouracil

amiodarone cimetidine azole antifungals ritonavir

drug inhibitors metabolism is most likely to be involved with?

inhibit

drugs that _______ intestinal P-gp mimic drug metabolism inhibitors by inc bioavailability; coadministration of P-gp inhibitors may result in toxic plasma concentrations of drugs given at normally nontoxic dosage.

suicide inhibitors

drugs that are metabolized to products that irreversibly inhibit the metabolizing enzyme

digoxin, cyclosporine, saquinavir

drugs that are usually expelled by P-gp so more toxic when given with a p-gp inhibitor.

amine oxidation

epinephrine

glutathione conjugation

ethacrynic acid, reactive phase 1 metabolite of apap

2C19 inhibitors

fluconazole omeprazole SSRIs

xenobiotics

foreign chemical compounds

pharmacogenomic variation in drug metabolism

genetic variations in drug metabolism occur for many drugs. Specific differences have been defined for 1. succinylcholine and similar esters 2. procainamide and similar amines 3. miscellaneous group that includes beta blockers, antidepressants and others

esters, amides

hydrolyses

p450 dependent oxidation

hydroxylation n-dealkylation o-dealkylation n-oxidation s-oxidation deamination

mdr-1

important modulator of intestinal drug transport and usually functions to expel drugs from the intestinal mucosa into the lumen thus contributing to presystemic elimination.

induction

increased rate and extent of metabolism of drugs

amides

indomethacin lidocaine procainamide

heme

induction usually results from inc synthesis of CYP450 enzymes in the liver as well as the cofactor, ____.

3A4 inhibitor inhibits

inhibitor antiarrhythmics antidepressants azole antifungals benzodiazepines calcium channel blockers cyclosporine delavirdine doxorubicin efavirenz erythromycin estrogens HIV protease inhibitors nefazodone paclitaxel proton pump inhibitors STATINS rifabutin rifampin sildenafil SSRIs tamoxifen trazodone vinca alkaloids

verapamil, mibefradil, furanocoumarin of grapefruit juice

inhibitors of P-gp

apap

is conjugated to harmless glucuronide and sulfate metabolites when it is taken in recommended doses by patients with normal live function.

amine oxidation, dehydrogenation

p450 independent oxidation

selective

phase 1 enzymes are not highly ________ in their substrates, so a small number of P450 isoforms are able to metabolize thousands of drugs.

oxidation, reduction, deamination, hydrolysis

phase 1 reactions include these reactions?

phase 1 rxns

reactions that convert the parent drug to a more polar or more reactive product by unmasking or inserting a polar functional group such as -OH, -SH, or -NH2

phase 2 rxns

reactions that inc water solubility to conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate.

enzyme induction

stimulation of drug-metabolizing capacity; usually manifested in the liver by inc synthesis of smooth endoplasmic reticulum (which contains high concentration of phase I enzymes)

glucuronate, acetate, glutathione, glycine, sulfate, methyl

subgroups that get added -OH, -NH2, -SH during phase 2

ethinyl estradiol, norethindrone, spironolactone, secobarbital, allopurinol, fluroxene, propylthiouracil

suicide inhibitors?

phase 2

synthetic reactions that involve addition of subgroups to -OH, -NH2, -SH

less lipid soluble, less readily reabsorbed forms

the body hastens excretion by transforming drugs to?

liver

the most important organ for drug metabolism is?

metabolic pathways

to ensure elimination of pharmacologically active xenobiotics and to terminate the action of many endogenous substances, evolution has provided __________ _______ that alter such compounds' activity and their susceptibility to excretion.

75%

what percentage of phase 1 enzymes of reactions does cyp3a4/cyp2d6 do?

sulfhydryl donors

what should be given for overdose of apap?

apap

when taken in a large quantity the pathways can become overwhelmed then the reactive intermediate combines with sulfhydryl groups on essential hepatic cell proteins resulting in cell death

smooth er of liver

where are phase 1 enzymes found?