Med Chem Unit 6

Define 'xenobiotics' as described in the context of drug metabolism.

Exogenous substances to which humans are exposed, such as ingested chemicals, inhaled smoke, or topical cosmetics.

What is the primary physiological purpose of drug metabolism?

To protect the body from potentially harmful chemicals by converting them into hydrophilic metabolites for excretion.

Which branch of pharmacology describes the 'dose-concentration relationship' or what the body does to the drug?

Pharmacokinetics (PK).

Which branch of pharmacology describes the 'concentration-effect relationship' or what the drug does to the body?

Pharmacodynamics (PD).

In pharmacokinetics, what is the primary route or mechanism of drug elimination?

Metabolism.

List the four main components of Pharmacokinetics often represented by the acronym ADME.

Absorption, Distribution, Metabolism, and Excretion.

Which organ is considered the most prominent and primary site of drug metabolism?

The liver.

Which organ is considered the primary site of drug excretion?

The kidney.

Where are drugs or metabolites typically excreted when they pass through the liver into the bile?

Into the intestines (and ultimately the feces).

Besides the liver, name three other tissues that contain drug-metabolizing enzymes.

Intestine, kidneys, and lungs (also brain, plasma, and skin).

What are the two main chemical purposes of drug metabolism regarding drug action?

Inactivation (preventing target interaction) and solubilization (preparing for excretion).

How does metabolism usually affect a drug's ability to interact with its target receptor?

It modifies the chemical structure, often preventing the drug from binding to the target biological molecule.

Term: Prodrug

Definition: An inactive drug that must be metabolized into an active metabolite to exert its pharmacological effect.

Metabolism usually makes a drug more _____, which promotes its removal by the kidneys.

Hydrophilic (or polar).

Term: Bioavailability

Definition: The fraction of an administered dose that reaches the systemic circulation.

Term: Clearance

Definition: A pharmacokinetic parameter describing the relationship between drug concentration and the rate of elimination.

What is 'first-pass metabolism'?

The intestinal and liver metabolism of an orally administered drug that occurs before it reaches systemic circulation.

How do 'inducers' affect drug-metabolizing enzymes compared to 'inhibitors'?

Inducers increase the expression of the enzyme, whereas inhibitors decrease the enzyme's activity.

In a drug-drug interaction, if Drug A inhibits the enzyme that metabolizes Drug B, what happens to the blood concentration of Drug B?

The concentration of Drug B increases.

Why does increasing the polarity of a metabolite promote urinary excretion?

Polar and charged molecules cannot easily cross lipid membranes to be reabsorbed from the renal tubules back into the blood.

What are the three main types of Phase I metabolism reactions?

Oxidation, Reduction, and Hydrolysis.

What is the most common Phase I metabolism reaction?

Oxidation.

Phase II metabolism is also known as _____ reactions.

Conjugation.

What is the most common Phase II metabolism reaction?

Glucuronidation (or glucuronic acid conjugation).

True or False: Phase I metabolism must always occur before Phase II metabolism.

False (Phase II can occur directly if the drug already has the necessary functional groups).

Which transporters facilitate the uptake of glucuronide and sulfate conjugates into renal cells?

Organic Anion Transporters (OATs).

Which transporters facilitate the efflux of conjugates into bile or urine?

Multidrug Resistance-associated Proteins (MRPs) or Breast Cancer Resistance Protein (BCRP).

Why does P-glycoprotein ($Pgp$) NOT play a significant role in transporting glucuronide conjugates?

$Pgp$ has a negatively charged substrate binding pocket, which repels negatively charged conjugates.

What percentage of clinical drugs are estimated to be eliminated primarily by metabolism?

70-80%.

Rank the three routes of drug elimination (Renal, Bile, Metabolism) from most common to least common.

Metabolism > Renal > Bile.

Of the drugs eliminated by metabolism, which enzyme family is responsible for approximately $52.5\%$ of that metabolism?

Cytochrome $P450s$ (CYPs).

What percentage of drugs are eliminated via the renal route without being metabolized first?

20-30%.

Name the three components required for Cytochrome $P450$ catalysis mentioned in the learning objectives.

The CYP enzyme, Heme, and Cytochrome $P450$ reductase.

In the CYP naming convention (e.g., $CYP1A2$), what does the '1' represent?

The genetic family.

In the CYP naming convention (e.g., $CYP1A2$), what does the 'A' represent?

The genetic subfamily.

In the CYP naming convention (e.g., $CYP1A2$), what does the '2' represent?

The specific gene/isoform.

In terms of cellular location, where are CYP enzymes primarily found within the cell?

In the lipid bilayer of the smooth endoplasmic reticulum.

Besides drug metabolism, what role do CYP enzymes play regarding cholesterol?

They are involved in cholesterol metabolism and the synthesis of steroid hormones.

Which Phase I reaction involves the removal of an alkyl group from a nitrogen atom?

$N$-dealkylation.

Which type of amine (primary, secondary, or tertiary) is most likely to undergo oxidative deamination?

Primary amines.

Which Phase I reaction involves the addition of oxygen to a sulfur atom?

$S$-oxidation.

Which Phase I reaction involves the removal of a halogen (e.g., fluorine, chlorine) from a molecule?

Dehalogenation.

Term: Hydrolysis

Definition: The cleavage of a chemical bond by the addition of water.

Which functional group is generally more susceptible to hydrolysis: esters or amides?

Esters.

What is the significance of hydrolysis regarding a drug's shelf-life?

It affects chemical stability, as drugs containing esters or amides can degrade over time in the presence of moisture.

Identify the two products formed by the hydrolysis of an ester.

A carboxylic acid and an alcohol.

Identify the two products formed by the hydrolysis of an amide.

A carboxylic acid and an amine.

What is the primary transferase enzyme responsible for Phase II glucuronidation?

UDP-glucuronosyl transferase (UGT).

What is the essential cofactor required for glucuronidation reactions catalyzed by UGT?

Uridine diphosphate glucuronic acid (UDPGA).

What is the essential cofactor required for sulfate conjugation catalyzed by Sulfotransferases (SULT)?

3'-phosphoadenosine-5'-phosphosulfate (PAPS).

True or False: Di-glucuronide conjugates (two glucuronic acids on one molecule) are common metabolic products.

False (glucuronidation of one functional group is usually sufficient for excretion).

What is the typical molecular weight threshold for a glucuronide conjugate to be excreted into the bile instead of urine?

Greater than $500$.

At physiological pH, what is the charge of a glucuronic acid conjugate ($pK_a \sim 3$)?

Negatively charged (deprotonated).

Which Phase II reaction is particularly important for drugs containing primary aromatic or aliphatic amines but does NOT increase water solubility?

$N$-acetylation.

Name the enzyme family responsible for $N$-acetylation.

$N$-acetyltransferases (NAT).

Which Phase II enzyme family is involved in the conjugation of glutathione to electrophilic drugs or metabolites?

Glutathione S-transferases (GST).

What is the role of Methyltransferases in drug metabolism?

They catalyze the addition of a methyl group to a drug or metabolite.

List the three types of reactions categorized under Phase I Metabolism.

Oxidation, Reduction, and Hydrolysis.

Which enzyme group follows CYPs as the second most common for clinical drug metabolism, accounting for about $11.7\%$?

UDP-glucuronosyl transferase (UGT).

What is the relationship between tizanidine and ciprofloxacin regarding CYP1A2?

Tizanidine is a substrate of CYP1A2, and ciprofloxacin is a potent inhibitor of CYP1A2.

In the Tizanidine/Ciprofloxacin example, why is co-administration contraindicated?

Inhibition of CYP1A2 by ciprofloxacin leads to toxically high blood concentrations of tizanidine.

Phase I reactions typically involve 'adding or exposing' _____.

Polar functional groups.

True or False: Some drugs are sufficiently water-soluble that they require no metabolism and are excreted unchanged.

True.

Under what condition can a drug undergo Phase II metabolism without needing a Phase I reaction first?

If the drug already contains functional groups that can be directly conjugated (e.g., a hydroxyl or amine group).

Why must glucuronide and sulfate conjugates rely on transporters for excretion?

They are negatively charged and cannot simply diffuse across cell membranes.

What is the primary site of excretion for drug metabolites after they have been made polar by the liver?

The kidneys (urine).

Which Phase I reaction converts an ester into a carboxylic acid and an alcohol?

Ester hydrolysis.

Which Phase I reaction converts an amide into a carboxylic acid and an amine?

Amide hydrolysis.

Explain the naming 'dealkylation' in the context of a metabolite.

It refers to the removal of an alkyl group, with the metabolite named based on the atom the group was removed from (e.g., $N$-dealkylated).

Define 'Oxidation' in the context of drug metabolism.

A reaction that increases the number of carbon-oxygen bonds or decreases the number of carbon-hydrogen bonds.

Which Phase II reaction uses Acetyl-CoA as a likely source of the added group (implied by N-acetylation)?

$N$-acetylation.

List four common Phase II enzymes.

UGT, SULT, NAT, and GST (also Methyltransferases).

What determines the frequency of drug administration in the context of metabolism?

The rate at which a drug is metabolized and eliminated from the body.

How does the 'solubilizing' purpose of metabolism facilitate biliary excretion?

It often involves adding large, polar groups (like glucuronic acid) that transporters recognize for efflux into bile.

What is the role of 'Heme' in CYP enzymes?

It is the iron-containing prosthetic group that acts as the site for oxygen binding and activation during catalysis.

Which Phase I enzyme is responsible for the hydrolysis of Succinylcholine?

Esterase (butyrylcholinesterase).

What characterizes an 'active metabolite'?

A metabolite that retains or possesses pharmacological activity, potentially contributing to the drug's effect or toxicity.

What are the two genetic families of UGT enzymes?

UGT1 and UGT2.

Briefly describe the mechanism of 'base hydrolysis' of an ester.

Hydroxide ($OH^-$) acts as a nucleophile, attacking the carbonyl carbon to displace the alcohol group.

The ability of an enzyme to catalyze 'acid hydrolysis' typically involves providing a _____ to the carbonyl oxygen.

Proton ($H^+$).