MedChem Exam 2

Transporters, Reaction Types, Phase 1-2 enzymes

What Transporters does this drug taken up?

Paracellular Transporter

e.g. Levothyroxine (40-80% BA)

What Transporters does this drug taken up

Paracellular Transporter

e.g. Desmopressin (0.16% BA)

Carrier-mediated or Active Transport can take up drugs in the ___ or _____, where uptake of ______________

gut or intestinal epithelial cells

uptake of endogenous nutrients, ions, and occasionally drugs (looks like endogenous nutrients, ions, amino acids, oligopeptides, phosphate).

What Transporters does this drug taken up?

Amino Acid transporter (active transporters)

What Transporters does this drug taken up?

Amino Acid transporter (active transporters)

What Transporters does this drug taken up?

Phosphate transporter (active transporters)

What Transporters does this drug taken up?

Oligopeptide Transporter (active)

What Transporters does this drug taken up?

Oligopeptide Transporter (active)

What Transporters does this drug taken up?

Oligopeptide Transporter (active)

After the calculation, what percent of drugs can passively diffuse? Is it effective?

Using the same logic as above:
b. At pH 7 = 10% is neutral and can cross by passive
diffusion
c. At pH 10 = 99% neutral and can cross by passive
diffusion

After the calculation, what percent of drugs can passively diffuse? Is it effective?

Using the same logic as above:
b. At pH 7 = 0.1% is neutral and can cross by passive
diffusion
c. At pH 10 = 0.0001% is neutral and can cross by passive
diffusion

Name reaction and enzyme

Aromatic hydroxylation & CYP 450

Name reaction and enzyme

Aliphatic Hydroxylation;CYP 450

Name reaction and enzyme

Epoxidation; CYP 450

Name reaction and enzyme

S-oxidation; CYP 450

Name reaction and enzyme (Cofactor)

Alcohol Oxidation; alcohol dehydrogenase or CYP 450 & H₂O as side product

Cofactor: NAD+

acetaldehyde

Name reaction and enzyme (Cofactor)

Aldehyde Oxidation; aldehyde dehydrogenase or CYP 450

Cofactor: NAD+

Name reaction and enzyme

N-oxidations; CYP 450 or FMO

Name reaction and enzyme

O-dealkylation; cyp 450

Name Reaction and Enzyme 

N-dealkylation; cyp 450

Name Reaction and Enzyme

Oxidative Deamination; CYP 2D6

Name reaction and enzyme

Dehalogenation; CYP 450

Name Enzyme 

3A4: high volume, lipophilic, structurally diverse, 1-2 H bond donors/acceptors at 5.5-7.5 Å and 8-10 Å from the site of metabolism

• numerous lipophilic Phe residues around the site of metabolism

Name Enzyme 

3A4: high volume, lipophilic, structurally diverse, 1-2 H bond donors/acceptors at 5.5-7.5 Å and 8-10 Å from the site of metabolism

• numerous lipophilic Phe residues around the site of metabolism

Name Enzyme 

3A4: high volume, lipophilic, structurally diverse, 1-2 H bond donors/acceptors at 5.5-7.5 Å and 8-10 Å from the site of metabolism

• numerous lipophilic Phe residues around the site of metabolism

Name Enzyme 

3A4: high volume, lipophilic, structurally diverse, 1-2 H bond donors/acceptors at 5.5-7.5 Å and 8-10 Å from the site of metabolism

• numerous lipophilic Phe residues around the site of metabolism

Name Enzyme 

3A4: high volume, lipophilic, structurally diverse, 1-2 H bond donors/acceptors at 5.5-7.5 Å and 8-10 Å from the site of metabolism

• numerous lipophilic Phe residues around the site of metabolism

Name Enzyme 

3A4: high volume, lipophilic, structurally diverse, 1-2 H bond donors/acceptors at 5.5-7.5 Å and 8-10 Å from the site of metabolism

• numerous lipophilic Phe residues around the site of metabolism

Name Enzyme 

3A4: high volume, lipophilic, structurally diverse, 1-2 H bond donors/acceptors at 5.5-7.5 Å and 8-10 Å from the site of metabolism

• numerous lipophilic Phe residues around the site of metabolism

Name Enzyme 

2D6: away from basic (nitrogen), relatively hydrophilic, a H-bond donor/acceptor at 5-7 A from site of metabolism

Name Enzyme 

2D6: away from basic (nitrogen), relatively hydrophilic, a H-bond donor/acceptor at 5-7 A from site of metabolism

Name Enzyme 

2D6: away from basic (nitrogen), relatively hydrophilic, a H-bond donor/acceptor at 5-7 A from site of metabolism

Name Enzyme 

2D6: away from basic (nitrogen), relatively hydrophilic, a H-bond donor/acceptor at 5-7 A from site of metabolism

Most CYP2D6 substrates are characterized by a basic nitrogen atom located approximately 5 to 7 Å from the site of oxidation.

Name Enzyme 

2D6: away from basic (nitrogen), relatively hydrophilic, a H-bond donor/acceptor at 5-7 A from site of metabolism

Name Enzyme 

2C9: weakly acidic, lipophilic, 1 or 2 H-bond donor/acceptor at 5-8 Å from the site of metabolism

• Interact with COO- /COOH

Name Enzyme 

2C9: weakly acidic, lipophilic, 1 or 2 H-bond donor/acceptor at 5-8 Å from the site of metabolism

• Interact with COO- /COOH

Name Enzyme 

2C9: weakly acidic, lipophilic, 1 or 2 H-bond donor/acceptor at 5-8 Å from the site of metabolism

• Interact with COO- /COOH

Name Enzyme 

2C9: weakly acidic, lipophilic, 1 or 2 H-bond donor/acceptor at 5-8 Å from the site of metabolism

Name Enzyme 

2C9: weakly acidic, lipophilic, 1 or 2 H-bond donor/acceptor at 5-8 Å from the site of metabolism

imide group (two carbonyl stabilize the molecule, resulting more acidic than amide)

Name Enzyme 

2C9: weakly acidic, lipophilic, 1 or 2 H-bond donor/acceptor at 5-8 Å from the site of metabolism

Electron-withdrawing effect of the sulfonyl group: A sulfonyl group contains two oxygen atoms, which are highly electronegative. This creates a strong electron-withdrawing effect

Name Enzyme and Reaction

Aromatic Hydroxylation; CYP 2D6

Name Enzyme and Reaction

Aromatic Hydroxylation; CYP 2C9

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) groupv

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

1A2: planar aromatic and/or heterocyclic amines and amides and polycyclic aromatic hydrocarbons, neutral or basic, lipophilic, preferably with one H-bond donor (XH) group

Name Enzyme 

MAO: monoamine oxidase ; neurotransmitter

Name Enzyme 

MAO: monoamine oxidase ; neurotransmitter

Name Enzyme 

MAO: monoamine oxidase ; neurotransmitter

Name Enzyme 

MAO: monoamine oxidase ; neurotransmitter

Name Enzyme 

FMO: Flavin monooxygenase

Name Enzyme

Carbonyl Reductase (carbonyl to OH)

Name Enzyme

amidase (amine to carboxylic acid 

Name Enzyme

Esterase (ester to carboxylic acid and amides)

Name Enzyme

Carboxylic Esterase (carboxylic acid)

• Overlapping substrate specificities (i.e. fairly promiscuous)
  • Ubiquitously expressed
  • Commonly counted on to convert prodrugs to active drugs

Name Enzyme

Carboxylic Esterase (carboxylic acid)

• Overlapping substrate specificities (i.e. fairly promiscuous)
  • Ubiquitously expressed
  • Commonly counted on to convert prodrugs to active drugs

Name Enzyme

Carbonyl Reductase ( carbonyl to OH) 

Active Transporter

At pH 5.4, 50% of the drug is protonated and 50% unprotonated.

At pH 6.4, 10% of the drug is protonated and 90% unprotonated.

At pH 7.4 (bloodstream pH), 1% of the drug is protonated and 99% unprotonated.

This molecule is described as an acid and a protonated acid (HA) is uncharged and can passively diffuse.  But the unprotonated form of an acid (A-) is charged and cannot passively diffuse.

Thus only 1% of the drug can passively diffuse across a membrane.

Alternatively you could have used the Henderson-Hasselback equation to arrive at essentially the same answer.

Make sure you could do this 1) for either an acid or base and 2) that you could recognize an acid or base if given the structure instead of being told which the compound was.

hydroxylation and N-demethylation; CYP3A4

This large macrolide antibiotic named clarithromycin (left) is biotransformed to both an N-demethylated metabolite (top) and a hydroxylated metabolite (bottom right).  The size and flexibility of this compound suggests that CYP3A4 is the most likely CYP enzyme to perform these reactions.

Because of differences in drug metabolism, elderly patients may require medication doses that are ______ compared to young adults.

Less frequent or lower dose

Elderly patients tend to metabolize some drugs more slowly than young adults (see "(Some) Factors Affecting Drug Metabolism").  Since these drugs remain in the bloodstream longer, less frequent dosing may be appropriate.

GST

GST is glutathione S-transferase, which adds glutathione.  Glutathione is a 3-amino acid peptide composed of glutamine-cysteine-glycine where the glutamine is connected to Cys via the Gln side chain and not the normal backbone connection.

UGT

You should recognize this structure as the nucleotide uridylate (uridine base + ribose sugar + two phosphates) with a sugar (carbohydrate) added to the terminal 5' phosphate, which is UDP-glucose.  UDP-glucose is used by UDP-glucuronyl transferase (UGT) to add the sugar part to a drug substrate.

Which enzyme shares the following characteristics with ALDH:  uses NAD+ and is a dehydrogenase.

ADH is alcohol dehydrogenase, which is obviously a dehydrogenase and it uses NAD+ to perform this reaction.

The drug will be more slowly metabolized.

Which of the following transporter superfamilies is primarily responsible for the efflux of drugs and their metabolites out of cells?

ABC superfamily primarily involves in the efflux of drugs from cell

UGT

SULT

Which of the following is primarily involved in the drug or small molecule efflux from cells?

PGP or P-glycoprotein or ABCB1 or MDR1 is a member of the ABC (ATP-binding cassette) superfamily which is primarily involved in efflux from cells.

P450

Flavin

The structure consists of the adenylate nucleotide linked to a flavin, and thus is flavin adenine dinucleotide or FAD.  The only metabolism enzyme we studied that uses FAD is flavin monooxygenase or FMO.

GST

A patient is prescribed a drug that is primarily inactivated by CYP3A4. The patient is also taking a second medication that is a known inducer of CYP3A4. What is the expected outcome?

The drug will be cleared more quickly, potentially falling below the therapeutic level.

A prodrug is prescribed that is activated by a CYP3A4.  The CYP3A4 inhibitor ritonavir is concurrently prescribed.  What is the expected outcome?

 

1. less pharmacological effect from the prodrug

2. the prodrug will work the same as if ritonavir was not also being dosed

3. increased pharmacological effect from the prodrug

4. Ritonavir would be metabolized faster than ususal

1. less pharmacological effect from the prodrug