medchem exam 2

What are the enteral routes of administration

oral, buccal/sublingual, and rectal

Based on the structure of the chemotherapeutic drug 5-fluorouracil, which mode of absorption is the most likely?

active transport (this can be recognized as a nucleoside analog, which is most likely to be taken up by nucleoside transporters.)

Based on the structure of the antidiuretic hormone desmopressin below, which mode of absorption is the most likely?

 

paracellular transport

A patient with a genetic polymorphism that results in them being a CYP2D6 "ultra-rapid metabolizer" would likely require ___________ doses of a drug primarily metabolized by CYP2D6 to achieve a therapeutic effect compared to a patient with normal metabolism. (lower or higher)

higher

What are parenteral routes of administration

IV bolus, IV infusion, SubQ, Intradermal, IM, intraarterial, intrathecal, intraperitoneal

What are the “other” forms about administration

transdermal and intranasal

what are the 3 major absorption routes

passive diffusion,  carrier-mediated/active transport, paracellular

What are some requirements for paracellular transport

1. needs good water solubility

2. can be charged

3. must be small

where does paracellular transport happen most

GI tract

what types of transport happen in the brain

passive diffusion and active transport. NO PARACELLULAR

how do drugs use active transport enzymes

drugs will mimic endogenous substrates such as amino acids, phosphates and oligiopeptides

explain requirements for drugs taken up by passive diffusion

• no energy required

• need appropriate lipid solubility to cross membrane (hydrophobic)

• lower MW (smaller molecules)

• NO CHARGE

how much of a drug needs to pass the membrane to be “effective”

10%

which versions of acids and bases can pass membranes (protonated or deprotonated)

protonated acids, and deprotonated bases. (neutral)

what is the pH of the saliva

6-7.5

what is the pH of the stomach

1-3

what is the pH of the blood

7.4

what is the pH of the sm. and lg. intestine

4-7

what is the pH of urine

4.5-8

what does the pKa value mean?

the pH where 50% of t he drug is ionized and 50% of the drug is unionized

what portion of acid is ionized and unionized when the pH is 1 point higher

90% is unionized and 10% is ionized

what portion of acid is ionized and unionized when the pH is 2 point higher

99% is unionized and 1% is ionized

what portion of acid is ionized and unionized when the pH is 3 point higher

99.9% is unionized and 0.1% is ionized

CP450’s. name the 4 we need to know

CYP1A2, CYP2D6, CYP2C9, CYP3A4 

what medications does CYP1A2 metabolize

planar, basic, big molecules

what medications does CYP2D6 metabolize

basic, hydrophilic, HBA or HBD 5-7A away from metabolism site.

what medications does CYP2C9 metabolize

weak acid, lipophilic, 1-2 HBA/HBD 5-8A away from metabolism site, 

what medications does CYP3A4 metabolize

high volume, lipophilic, 1-2 HBA or HBD at 5.5-7.5A and 8-10A away from metabolism site.

what are CYP450 inhibitors

drugs that block or slow down the activity of P450 enzymes. examples are ketoconazole and grapefruit juice, which increases the drug level in the blood (which could lead to toxicity) because its not being broken down.

What do CYP450 inducers do

increase the production of CYP450 enzymes, increasing metabolism which lowers the drugs level in the bloodstream making it less effective. 

what are the major P450 reactions

aromatic and aliphatic hydroxylation, epoxidation, S-oxidation, alcohol oxidation, aldehyde oxidation, N-oxidation, dealkylations, deamidations, dehalogenations.

3 classes of Phase 1 enzymes

1. Oxidating

2. Reducing

3. Hydrolyzing

What are the oxidating enzymes

CYP450, FAO, MAO, ADH, ALDH

What is FMO

• Flavin-containing Monooxygenase

• oxidizes @ N, S, and P to form N-oxides, sulfoxides, and phosphites

• in the liver, kidney and intestine

• in ER membrane of cells

• FAD prosthetic group

What is MAO

• Monoamine oxidases

• liver, intestine

• FAD prosthetic group

• IN MITOCHONDRIA (M for Mitochondria)

• endogenous and xenobiotics

• mainly primary amine substrates

What is ADH

• Alcohol dehydrogenase

• use NAD+ or NADPH

• oxidizes xenobiotic alcohols to aldehydes

What is ALDH

• Aldehyde dehydrogenase

• converts aldehydes into carboxylic acids

• also uses NAD+ or NADPH

What are the reducing phase 1 enzymes

• CYP reductase

• Azo and nitro reductase

• carbonyl reductase

what is the most common reducing phase 1 enzyme

• carbonyl reductase

what do carbonyl reductases do

• turn carbonyls into hydroxyls

What are the phase 1 hydrolyzing enzymes

• epoxide hydrolase

• esterases

• amidases

what do esterases do

cleaves a molecule at the ester bond

what do amidases do?

cleave the molecule at the amide

what are carboxylesterases

• a subset of esterases

• cleave esters into carboxylic acids

which phase of metabolism effects the drugs hydrophilicity the most

the second phase has the most effect on the water solubility of the drug (larger molecules are added) 

what are the 2 main groups of phase 2 enzymes

electrophilic and nucleophilic

what are the phase 2 enzymes

UDP-glucuroryl transferase (UGT), sulfotransferase (SULT or ST), N- and O-methyl transferase, acetyl transferases, amino acids tranferases

what is the nucleophilic phase 2 enzyme

Glutathione S-transferase (GST)

what does UGT do??

adds a sugar molecule to any xenobiotic (makes more polar)

what does SULT/ST do

• sulfotransferase

• adds sulfate group to xenobiotic

• amine or hydroxyl

What is GST

• glutathione s-transferases

• glutathione added to xenobiotic

what are the 2 groups of phase 3 enzymes

• ABC (ATP-binding cassette)

• SLC (solute carrier)

what are the common ABC transporters

• P-glycoprotein (PGP)

• ABCC’s

• ABCG2

What are the 3 SLC trasnporters

1. OATP (organic anion transporter polypeptides)

2. OAT (organic anion transporter)

3. OCT (organic cation transpoerter)

which group of phase 3 transporters do efflux

ABC enzymes

which group of phase 3 transporters mainly are used for influx

SLC: primarily uptake molecules into cell (influx)

what are the two ways to excrete the medication

renal and bile excretion

what happens after drugs are metabolized in the liver

they go into the bile in the bile canaliculus, then out into the intestines and feces.

what is enterohepatic cycling

the drug is metabolized in the liver and goes into the bile and gut where certain enzymes reconvert the metabolites into lipophilic versions so they can be reabsorbed into the plasma. this increases duration of action (could be good, could be bad)

what is this molecule a cofactor for

UGT

what enzyme adds a sugar group to a xenobiotic

UGT

what enzyme adds glutathione to a xenobiotic

GST

where does the xenobiotic bind to GSH after GST is used to attach it

to the Sulfur of cysteine

which enzymes use water to perform hydrolysis during metabolism

esterase’s and amidases

when a prescribed drug is metabolized by CYP3A4 and the patient is also taking an OTC CYP3A4 inhibitor, what is the outcome?

The prescribed medication will not be metabolized as quickly leading to lower therapeutic effect, and levels will increase in the blood, which could cause toxicity.

The following reaction is performed by which enzyme?

SULT (or ST)

The compound below is a co-substrate or cofactor for which drug metabolism enzyme?

P450’s! The structure is Heme

A person is a CYP2D6 poor metabolizer and they are prescribed a CYP2D6 drug substrate.  What is the expected outcome compared to someone who has at least one normally-functioning copy of CYP2D6?

The drug will be more slowly metabolized.

What phase I enzyme shares the following characteristics with P450:  monooxygenase, found in the liver, uses O2, forms N-oxides

FMO

Which route of administration is both the safest and easiest for patients?

Oral

This HIV drug zidovudine looks a lot like what endogenous substance? What transporter would take this molecule? 

It is very structurally similar to a nucleotide, causing it to be taking up by an active transporter (probably a SLC)

What category of cytochrome P450 metabolic reaction is depicted?  Which of the major drug-metabolizing cytochrome P450 enzymes is most likely to be involved?  

expoxidation; CYP1A2

Which is a rapid administration method with variable dose absorption which also has limitations on penetration into the tissue particularly depending on the physical size of the drug particles (not drug molecular weight)?

Inhalation

Based on its structure below, you would most likely expect that fentanyl would be most likely absorbed by which route?

passive diffusion. this drug is highly lipophilic and no charge, so it will easily diffuse.

What category of cytochrome P450 metabolic reaction is depicted?  Which of the major drug-metabolizing cytochrome P450 enzymes is most likely to be involved?

O-dealkylation: CYP2D6 (The molecule is basic and relatively hydrophilic)

Based on its structure below, you would expect that the artificial sweetener aspartame would be most likely absorbed by which of the following routes?

 

active transport by a oligopeptide transporter