Chap 4 Drug Metabolism Flashcards
Describe First Pass effect:
The oral route of administration entails passage of the drug through:
- gastric
- intestinal contents
- the epithelium and other tissues of the intestinal wall
- portal blood
- the liver before it enters the systemic circulation for distribution to the body.
Metabolism by enzymes in any of these tissues, expulsion by drug transporters, and excretion into the bile all may contribute to the first-pass effect of oral administration.
Phase I reactions
Reactions that convert the parent drug to a more polar (water-soluble) or more reactive product by unmasking or inserting a polar functional group such as OH, SH, or NH2
Phase II reactions
Reactions that increase water solubility by conjugation of the drug molecule with a polar moiety such as glucuronate, acetate, or sulfate
CYP isozymes
Cytochrome P450 enzyme species (eg, CYP2D6 and CYP3A4) that are responsible for much of drug metabolism. Many isoforms of CYP have been recognized
Enzyme induction
Stimulation of drug-metabolizing capacity; usually manifested in the liver by increased synthesis of smooth endoplasmic reticulum (which contains high concentrations of phase I enzymes)
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
Examples of phase I drug-metabolizing reaction:
Name reaction type for:
Oxidations, P450 dependent
Oxidations, P450 dependent:
Hydroxylation
N-dealkylatioN
O-dealkylation
N-oxidation
S-oxidation
Name Typical Drug Substrates for Phase 1 drug metabolizing reaction types:
Oxidations, P450 dependent
Typical Drug Substrates1. Deamination
- Amphetamines, barbiturates, phenytoin, warfarin
- Caffeine, morphine, theophylline
- Codeine
- Acetaminophen, nicotine
- Chlorpromazine, cimetidine, thioridazine
- Amphetamine, diazepam
Examples of phase I drug-metabolizing reaction:
Name reaction type for:
Oxidations, P450 independent
Oxidations, P450 independent
- Amine oxidation
- Dehydrogenation
Name Typical Drug Substrates for Phase 1 drug metabolizing reaction types:
Oxidations, P450 independent
Oxidations, P450 independent
- Epinephrine
- Chloral hydrate, ethanol
Phase I drug-metabolizing reactions:
Reductions
(Name 4)
- Chloramphenicol
- clonazepam
- dantrolene
- naloxone
Phase I drug-metabolizing reaction type:
Hydrolyses
Esters
Amides
- Typical drug substrates* for
- Phase I drug-metabolizing* reaction type:
Hydrolyses
(Name 7)
- Aspirin
- clofibrate
- procaine
- succinylcholine
- Indomethacin
- lidocaine
- procainamide
xenobiotics
xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism.
It can also cover substances that are present in much higher concentrations than are usual
foreign chemical compounds found in the air, water, and food.
Oxidation reaction:
To cause an atom or group of atoms to lose electrons during a chemical reaction
Reduction reaction:
Reduction is chemical reaction that involves the gaining of electrons by one of the atoms involved in the reaction.
The term refers to the element that accepts electrons, as the oxidation state of the element that gains electrons is lowered
Hydrolysis:
Hydrolysis is a reaction involving the breaking of a bond in a molecule using water.
The reaction mainly occurs between an ion and water molecules and often changes the pH of a solution.
In chemistry, there are three main types of hydrolysis: salt hydrolysis, acid hydrolysis, and base hydrolysis.
Conjugation of the drug
The joining of a toxic substance with some natural substance of the body to form a detoxified product for elimination from the body.
Phase II reaction. These reactions involve covalent attachment of small hydrophilic endogenous molecule such as glucuronic acid, sulfate, or glycine to form water-soluble compounds, that are more hydrophilic.
Dealkylation:
The removal of alkyl groups from a compound.
Alkyl group is a type of functional group that has a carbon and hydrogen atom present in its structure. The general formula for an alkyl group is CnH2n+1, where n represents a number or integer.
Dehydrogenation
Dehydrogenation is a chemical reaction that involves the removal of hydrogen from an organic molecule.It is the reverse of hydrogenation
Biotransformation:
Biotransformation of drugs is one such process. It is an important mechanism by which the body terminates the action of many drugs
Phase I reactions include ___ type of reactions.
Name each:
total of 4
- oxidation (especially by the cytochrome P450 group of enzymes, also called mixed-function oxidases),
- reduction
- deamination
- hydrolysis
Where are enzymes found:
Name the Organ & Cellular structure
enzymes are found in high concentrations in the smooth endoplasmic reticulum of the liver.
which P450 isoform is responsible for the greatest number of important reactions
Of the drugs metabolized by phase I cytochrome P450s, approximately:
75% are metabolized by just two:
- CYP3A4/5
- CYP2D6
What type of reactions are (Phase II ractions)
&
involve additon of what subgroups
Phase II ractions are synthetic reactions that involve addition (conjugation) of subgroups to —OH, —NH2, and —SH functions on the drug molecule
Name subgroups of Phase II Reactions:
name 6:
The subgroups that are added include:
- gluc- uronate,
- cetate,
- glutathione,
- glycine,
- sulfate,
- methyl groups.
What are the phase II drug-metabolizing:
reaction types & drug substrates
Name all 6:
- Glucuronidation
Sub: Acetaminophen, diazepam, digoxin, morphine, sulfamethiazole
- Acetylation
Sub: Clonazepam, dapsone, isoniazid, mescaline, sulfonamides
- Glutathione conjugation
Sub: Ethacrynic acid, reactive phase I metabolite of acetaminophen
- Glycine conjugation
Sub: Deoxycholic acid, nicotinic acid (niacin), salicylic acid
- Sulfation
Sub: Acetaminophen, methyldopa
- Methylation
Sub: Dopamine, epinephrine, histamine, norepinephrine, thiouracil
What is the most important organ for drug metabolism ?
liver
Biotransformation of a drug may vary markedly among different individuals. This variation is most often due to what two factors :
Genetic or drug-induced differences
What is the primary determinant of clearance,
&
what must be considered carefully when designing or modifying a dosage regimen.
rate of biotransformation
variations in drug metabolism
Coadministration of certain agents may alter the disposition of many drugs,
Mechanisms include the following:
- Enzyme induction
- Enzyme inhibition
- Inhibitors of intestinal P-glycoprotein
Enzyme induction:
Induction (increased rate of activity and extent of metabolism) usually results from increased synthesis of cytochrome P450 drug-oxidizing enzymes in the liver as well as the cofactor, heme
What are the most common strong inducers of drug metabolism
- carbamazepine
- phenobarbital
- phenytoin
- rifampin
Enzyme inhibition
is a molecule that binds to an enzyme and decreases its activity.
Suicide Inhibitors:
is an irreversible form of enzyme inhibition that occurs when an enzyme binds a substrate analog and forms an irreversible complex with it through a covalent bond during the normal catalysis reaction
Ex of Suicide Inhibitors: 7
Such agents include:
- ethinyl estradiol
- norethindrone,
- spironolactone,
- secobarbital,
- allopu- rinol,
- fluroxene,
- propylthiouracil
Inhibitors of intestinal P-glycoprotein:
membrane-associated transport protein, an important element of the intestinal epithelium
P-glycoprotein contributes to the elimination of many drugs by mediating their direct secretion from the blood into the intestinal lumen
Describe the mechanism of hepatic enzyme induction :
list 3 drugs that are known to cause it:
Induction (increased rate and extent of metabolism) usually results from increased synthesis of cytochrome P450 drug-oxidizing enzymes in the liver as well as the cofactor, heme
Liver enlargement in response to hepatic enzyme induction is typically associated with hepatocellular hypertrophy and often, transient hepatocyte hyperplasia
- carbamazepine
- phenobarbital
- phenytoin
- rifampin
List 3 drugs that inhibit the metabolism of other drugs.
- amiodarone,
- cimetidine,
- furanocoumarins (present in grapefruit juice)
Describe some of the effects of smoking, liver disease, and kidney disease on drug elimination.
Smoking is a common cause of enzyme induction in the liver and lung and may increase the metabolism of some drugs.
Describe the Inhibitors of intestinal P-glycoprotein and its importantce
P-glycoprotein (P-gp), is an important modulator of intestinal drug transport and usually functions to expel drugs from the intestinal mucosa into the lumen, thus contributing to presystemic (first pass) elimination
P-gp and other members of the MDR family are found where:
P-gp and other members of the MDR family are also found in the blood-brain barrier and in drug-resistant cancer cells.
P-gp inhibitors
P-gp inhibitors include:
- 1.* verapamil
2. mibefradil (a calcium channel blocker no longer on the market )
3. furanocoumarin (components of grapefruit juice)
Drugs that inhibit intestinal P-gp
