DPM Pharmacology II meta_exc

A patient with liver disease receives an oral medication that normally undergoes extensive first-pass metabolism. Compared to a healthy individual, this patient will most likely experience:

• decreased drug bioavailability due to impaired hepatic function.
• increased drug bioavailability due to reduced first-pass metabolism.
• no change in drug bioavailability as first-pass metabolism occurs in the intestine.
• enhanced drug elimination through biliary excretion.
• accelerated renal clearance of the parent compound.

Answer explanation

In liver disease, reduced hepatic function leads to decreased first-pass metabolism, allowing more of the orally administered drug to reach systemic circulation, thus increasing bioavailability.

The cytochrome P450 system is characterized by all of the following EXCEPT:

• they are heme-containing isozymes found in most cells.
• they are mainly attached to the smooth endoplasmic reticulum of hepatocytes.
• they primarily function in Phase II conjugation reactions.
• they absorb light at 450 nm wavelength when exposed to carbon monoxide.
• they are responsible for most oxidative metabolism of drugs.

Answer explanation

Cytochrome P450 enzymes function primarily in Phase I metabolism (oxidation, reduction, hydrolysis), not Phase II conjugation reactions which are mediated by transferases.

A lipophilic drug is administered orally and must be eliminated from the body. The most likely sequence of events for this drug is:

• direct renal elimination without metabolic transformation.
• biliary elimination followed by hepatic metabolism.
• hepatic metabolism to hydrophilic metabolites followed by renal elimination.
• intestinal metabolism followed by fecal elimination.
• pulmonary elimination through expiration.

Answer explanation

Lipophilic drugs cannot be efficiently eliminated by kidneys, so they must first be metabolized by the liver to hydrophilic metabolites that can then be renally eliminated.

When analyzing drug-drug interactions involving cytochrome P450 enzymes, enzyme inducers will result in:

• increased drug concentrations and enhanced therapeutic effects.
• increased metabolism leading to decreased drug efficacy.
• decreased metabolism leading to increased toxicity.
• no significant change in drug pharmacokinetics.
• enhanced drug absorption from the gastrointestinal tract.

Answer explanation

Enzyme inducers activate CYP450 enzymes, leading to increased metabolism of substrate drugs, which results in decreased drug concentrations and reduced efficacy.

The primary difference between Phase I and Phase II drug metabolism is that Phase I:

• occurs only in the liver while Phase II occurs in multiple organs.
• always results in drug inactivation while Phase II activates drugs.
• introduces or unmasks polar groups while Phase II involves conjugation reactions.
• is mediated by transferases while Phase II uses cytochrome P450 enzymes.
• produces only hydrophilic metabolites while Phase II produces lipophilic products.

Answer explanation

Phase I metabolism introduces or unmasks polar groups (-OH, -NH2) through oxidation, reduction, or hydrolysis, while Phase II involves conjugation of these polar groups with endogenous substrates.

First-pass metabolism can occur at which of the following sites? I. Intestinal lumen II. Intestinal wall III. Liver IV. Gut microbiota

• I and II
• I, II, and III
• I and IV
• II and IV
• I, II, III, and IV

Answer explanation

First-pass metabolism can occur at all four sites: enzymatic degradation in intestinal lumen, CYP450 enzymes in intestinal wall, liver metabolism via portal circulation, and bacterial metabolism by gut microbiota.

A drug that inhibits cytochrome P450 enzymes is co-administered with another medication that is a substrate for the same enzyme system. The most likely clinical consequence is:

• enhanced elimination of the substrate drug.
• increased first-pass metabolism of both drugs.
• decreased metabolism of the substrate drug leading to potential toxicity.
• accelerated conversion to active metabolites.
• no interaction due to enzyme specificity.

Answer explanation

Enzyme inhibitors reduce CYP450 activity, leading to decreased metabolism of the substrate drug, resulting in increased drug concentrations and potential toxicity.

The biotransformation of drugs can be influenced by multiple factors. Which combination of factors would most likely result in altered drug metabolism in a clinical setting?

• molecular size and environmental temperature only.
• patient age and genetic polymorphisms only.
• patient age, disease states, and concurrent medications.
• drug color and tablet coating only.
• time of drug administration only.

Answer explanation

Patient age affects enzyme activity, disease states can alter metabolic capacity, and concurrent medications can induce or inhibit metabolizing enzymes, all significantly impacting drug biotransformation.

Regarding the distribution of cytochrome P450 enzymes, they are:

• exclusively located in hepatocytes with no extrahepatic distribution.
• mainly distributed in hepatocytes but also found in enterocytes of small intestine.
• primarily located in the kidneys for drug elimination.
• found only in the smooth endoplasmic reticulum of all cells.
• concentrated exclusively in the intestinal microbiota.

Answer explanation

CYP450 enzymes are mainly distributed in hepatocytes but also exist in extrahepatic sites, particularly enterocytes of the small intestine, and in smaller quantities in kidneys, lungs, and brain.

A compound that already contains polar groups such as -COOH or -OH will most likely:

• require extensive Phase I metabolism before elimination.
• undergo only cytochrome P450-mediated oxidation.
• bypass Phase I metabolism and proceed directly to Phase II or elimination.
• be eliminated exclusively through biliary excretion.
• require conversion to lipophilic metabolites for excretion.

Answer explanation

Compounds that already have polar groups don't need Phase I metabolism to introduce polarity, so they can proceed directly to Phase II conjugation or elimination if sufficiently polar.