Pharmacology: Drug Elimination and Hepatic Clearance

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Questions and Answers

What is the consequence of the metabolic differences in humans and dogs regarding phenytoin?

It causes a complete inhibition of drug activity.

It indicates a largely deaminated metabolism. (correct)

It results in decreased formation of 6'b-hydroxy lovastatin.

It leads to increased side effects in all populations.

Which phenotypes were identified in relation to drug metabolism?

Normal Metabolizer and High Metabolizer.

Fast Metabolizer and Slow Metabolizer.

Efficient Metabolizer and Poor Metabolizer. (correct)

Rapid Metabolizer and Minimal Metabolizer.

What factor is suggested to influence the variations in metabolism among different populations?

Racial differences among populations.

Dietary habits unique to each region.

Physical activity levels of individuals.

Geographic rather than racial factors. (correct)

What side effect observation was noted specifically among Japanese subjects taking mephobarbital?

Higher overall incidence of side effects. Signup and view all the answers

Which CYP isoenzyme inhibitors affect the formation of 6'b-hydroxy lovastatin?

Cyclosporine and ketoconazole. Signup and view all the answers

Which CYP enzyme is responsible for the metabolism of simvastatin?

CYP3A Signup and view all the answers

Which of the following drugs is a substrate for CYP2C19?

Omeprazole Signup and view all the answers

What is the role of CYP enzymes in drug metabolism?

They catalyze oxidation and other reactions to facilitate drug metabolism. Signup and view all the answers

S-Warfarin is primarily metabolized by which CYP enzyme?

CYP2C9 Signup and view all the answers

Which drug listed below is a substrate for CYP2D6?

Desipramine Signup and view all the answers

What is the role of CYP450 in drug metabolism?

It is a heme protein responsible for drug transformation. Signup and view all the answers

Which factor does NOT influence drug metabolism?

Food intake Signup and view all the answers

What is the function of phospholipid in the context of drug metabolism?

It binds the drug molecule to CYP450. Signup and view all the answers

Allopurinol functions by which mechanism?

Inhibiting xanthine oxidase activity. Signup and view all the answers

The conversion of a drug to a more polar metabolite is significant because it:

Enables quicker elimination of the drug. Signup and view all the answers

What is a consequence of using intravenous administration of isoproterenol?

It leads to rapid metabolism to the 3-O-methylated metabolite. Signup and view all the answers

Which transporter is considered the most well understood in drug development?

P-glycoprotein (Pgp) Signup and view all the answers

What is assumed to be constant in the hepatic clearance model within the same subject?

Intrinsic clearance Signup and view all the answers

Reduced NADPH is required in the drug metabolism process primarily for:

Providing reducing equivalents for reactions. Signup and view all the answers

What role do hepatic parenchymal cells play in drug metabolism?

They contain microsomal fractions that participate in metabolism. Signup and view all the answers

Which combination of drugs has a known interaction involving drug transporters?

Fexofenadine and ketoconazole Signup and view all the answers

What can modify intrinsic clearance according to patient variability?

Enzymatic induction or inhibition Signup and view all the answers

Which of the following transport proteins is specifically involved in organic cation transport?

Organic cation transporter (OCT) Signup and view all the answers

The combined effect of efflux and CYP inhibition can lead to what kind of clinical outcome?

Severe adverse reactions Signup and view all the answers

Which drug is known to interact with quinidine?

Digoxin Signup and view all the answers

What type of drug interactions can be assessed using CYP450 subfamilies?

Both metabolic and transporter-based interactions Signup and view all the answers

Which of the following best describes epoxides?

They are highly reactive and can cause liver necrosis or cancer. Signup and view all the answers

What is a significant consequence of acetylation reactions in drug metabolism?

The product may precipitate in the kidneys and cause damage. Signup and view all the answers

What factor is NOT listed as contributing to the limited capacity of certain conjugation pathways?

Limited availability of the parent drug. Signup and view all the answers

Which of the following options correctly identifies a common phase II reaction?

Glucuronidation Signup and view all the answers

N-acetylprocainamide is formed through the acetylation of which drug?

Procainamide Signup and view all the answers

Which statement correctly describes the genetic polymorphism observed in acetylation reactions?

There are subpopulations that can be classified as fast and slow acetylators. Signup and view all the answers

What characterizes drugs that undergo glucuronidation?

They are excreted rapidly in bile or urine. Signup and view all the answers

Which of the following reactions is implicated in drug toxicity according to the information provided?

Acetylation Signup and view all the answers

Which compound is formed when salicylic acid is conjugated with glucuronic acid?

Salicylglucuronide Signup and view all the answers

What is the role of conjugating reagents in phase II reactions?

To form water-soluble metabolites for excretion. Signup and view all the answers

What is the primary function of the liver regarding drugs?

Drug elimination Signup and view all the answers

Which cells in the liver are responsible for engulfing worn-out RBC and foreign materials?

Kupffer cells Signup and view all the answers

Hepatic blood flow consists of which two major vessels?

Hepatic portal vein and hepatic artery Signup and view all the answers

What anatomical structure is the basic functional unit of the liver?

Liver lobule Signup and view all the answers

What percentage of the liver blood supply is carried by the hepatic artery?

25% Signup and view all the answers

Which of the following best describes the blood flow in the hepatic portal vein?

Carries blood from the digestive tract Signup and view all the answers

What happens to drug metabolism in the case of cirrhosis?

Blood flow and bioavailability change Signup and view all the answers

The average hepatic blood flow is approximately:

1.3-1.5 L/min Signup and view all the answers

Which factor can affect the metabolism of drugs in the liver?

Hydrodynamics of hepatic blood flow Signup and view all the answers

Which type of blood vessels in the liver are responsible for facilitating drug and nutrient exchange?

Sinusoids Signup and view all the answers

What characterizes the flow of drug metabolism in the liver?

It is flow- and site-dependent Signup and view all the answers

What does the term 'nonlinear kinetics' refer to in hepatic metabolism?

Variable drug elimination rates influenced by concentration Signup and view all the answers

Which organ is responsible for synthesizing and excreting bile acids?

Liver Signup and view all the answers

What is primarily drained by the common bile duct?

Bile and biliary excretion products Signup and view all the answers

Study Notes

Drug Elimination and Hepatic Clearance

Drug elimination is the decline in peak plasma concentrations due to metabolism and renal excretion.
The primary site of metabolism is the liver. Other sites include the lung, skin, gastrointestinal mucosa, distal ileum, large intestine, and kidneys.
Factors like renal and hepatic disease, and drug-drug interactions can affect drug elimination.
Variability in elimination half-lives exists for highly metabolized drugs, like phenytoin, theophylline, and lidocaine, due to genetic and environmental factors. Renal excretion variability is less for primarily renally excreted drugs.
Renal drug excretion depends on glomerular filtration rate (GFR) and kidney blood flow.
Hepatic clearance is the volume of blood that perfuses the liver, cleared of drug per unit of time.
First-order elimination means the rate of elimination is constant, with the sum of metabolism (km) and excretion (ke) rate constants. (k = km + ke).
Excretion rate constant (ke) is easily determined for drugs primarily removed by the kidneys.
The fraction (fe) of drug excreted unchanged in urine, and (1 - fe) fraction of drug metabolized, can be measured.
If renal pathways are impaired, hepatic metabolism becomes the primary elimination route; conversely, liver function decline leads to increased renal elimination.
Total body clearance (Cl+) refers to the sum of all clearances in the body, which represents the volume of blood or plasma from which a drug is completely removed per unit time.
Total body (systemic) clearance is used to measure how effectively the body eliminates drugs.

Enzyme Kinetics

The rate of metabolism is a first-order process, where plasma drug concentration is relatively high, and all enzyme molecules become complexed with drug.
The reaction rate becomes maximal (Vmax), when the substrate concentration (drug) is high and the rate proceeds at zero-order.
The Michaelis constant (KM) corresponds to the drug concentration when the reaction velocity is at half Vmax.
The Michaelis-Menten equation describes drug metabolism rate processes.
It assumes the drug and enzyme concentrations are both constant and an energetically favored drug-enzyme intermediate is initially formed.
When all the enzymes are saturated, rate is dependent on availability of enzymes, and then the reaction proceeds at zero order maximum velocity.

Biotransformation

Transformation of drug to metabolites, is a kinetic process, dependent on the drug's concentration and the corresponding enzyme saturation.
This process includes oxidation, reduction, hydrolysis, and conjugation reactions.
Drugs' metabolic rate and drug elimination half-life are correlated.
Key enzymes involved in biotransformation include mixed-function oxidases (MFOS).
Enzymes involved, like CYP450, are structural and an electron-transport system that requires: NADPH (NADPH2), Molecular oxygen, and CYP450/NADPH-CYP450 reductase.

Types of Enzyme Inhibition

Competitive: Inhibitor and drug compete for same active site on the enzyme (similar chemical structures).
Noncompetitive: Inhibitor binds to a different site on the enzyme (allosteric site).
Uncompetitive: Inhibitor interacts with enzyme-substrate complex.

Pharmacokinetics

Pravastatin, has variable bioavailability (50-60% for AUC and average of 34%)
Extensive first pass extraction in the liver (extraction ratio 0.66).
Cyclosporine significantly affects pravastatin by inhibiting hepatic transporters.
Drug-drug interactions should be monitored.

Drug-Drug interactions

Affecting drug metabolism.
Enzyme induction: increase in enzyme activity (e.g., Rifampin, Phenobarbital, Carbamazepine).
Enzyme inhibition: decrease in enzyme activity (e.g., Ketoconazole and Ranitidine).
Drug metabolism inhibition and induction is a known pharmacokinetic factor

Transporter-Based Interactions

These can include inhibitors or inducers of transporters.
Multidrug resistance protein, MDR1/P-gp, is a major transporter for digoxin.
P-gp inhibitors (e.g., Ritonavir and quinidine) can increase digoxin levels.

First-Pass Effect and Liver Extraction Ratio (ER)

A phenomenon whereby a drug absorbed from the GI tract is metabolized in the liver before systemic circulation. ER is associated with the fraction of drug removed from the blood by the liver.
For high ER drugs, a high percentage of the circulating drug is removed by the liver before reaching systemic circulation, leading to lower bioavailability. Conversely, low ER drugs are less affected by first-pass effect due to lower hepatic clearance.
Changes in liver blood flow affect hepatic clearance, which in turn can impact clinical outcome or dosing changes, as a result.

Species Differences

Genetic differences can significantly affect hepatic biotransformation enzymes.
This can lead to variations in drug metabolism rates between species (e.g., humans, rats, dogs).
Environmental factors can also contribute.

Specific Examples

Drugs like propranolol, morphine, ibuprofen, digoxin, theophylline, phenytoin, and others have been discussed for their hepatic clearance mechanisms.
Examples of enzyme inhibition and induction, and substrate/drug interactions, to affect metabolism have also been described.

Biliary Excretion

Drugs or their metabolites are secreted into bile and excreted through feces.
This process involves an active secretion process into the liver.
The rate of drug elimination is measured by monitoring compounds secreted into the Gl perfusate.
Factors like biliary secretion are relevant for appropriate dosing and clinical monitoring.

Liver Anatomy and Physiology

The liver is a major organ related to drug metabolism.
It has a complex structure with a highly vascularized network, which is crucial for its metabolic function.

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Description

This quiz focuses on key concepts related to drug elimination and hepatic clearance. You will explore the processes of metabolism, renal excretion, and factors that influence drug clearance. Understand the role of the liver and kidneys in pharmacokinetics and how genetic variability affects drug metabolism.