Lesson 7. Drug Metabolism

Drug Metabolism

irreversible conversion of a drug to a different substance in vivo by enzymatic catalysis or biochemical transformation of drug to metabolic products

liver

The principal site of drug metabolism is __________________.

largest

The liver is the a._______ internal organ and is the only organ capable of b._________.

a = ?

regeneration

The liver is the a._______ internal organ and is the only organ capable of b._________.

b = ?

Lung, Skin, GI Mucosal Cells, Microbiological Flora in the distal portion of the Ileum, Large Intestine, and Kidneys

Other sites of drug metabolism

drug elimination

PLASMA LEVEL-TIME CURVE:

• The decline from peak plasma concentrations after drug administration results from _______________ or removal by the body.

Biotransformation

DRUG IN THE BODY ARE REMOVED BY TWO PRIMARY SITES:

1. Metabolism by _______________

2. Excretion _____________

1 = ?

renally

DRUG IN THE BODY ARE REMOVED BY TWO PRIMARY SITES:

1. Metabolism by _______________

2. Excretion _____________

2 = ?

difference between k and ke

The rate constant for metabolism is difficult to measure directly and is usually obtained from the ______________________.

metabolism rate constant (Km)

sum of the rate constants for the formation of each metabolite

Liver

major organ responsible for drug metabolism

synthesizing and excreting organ

Liver is both a _________________________ as it can create and excrete bile.

basic anatomical unit

The liver lobule is the ________________________ of the liver.

Liver Lobule

contains parenchymal cells in a network of interconnected lymph and blood vessels

hepatocytes

Liver Lobules consists of different ___________________ that are arranged in a central vein.

flow and site

Drug Metabolism in the Liver has been shown to be _________________ dependent.

Hepatic Diseases, Genetic Differences in Enzyme Levels, and Environmental Factors

____________________________________ can affect half-lives of drugs eliminated by drug metabolism.

stomach

The left lobe of the liver is smaller than the right lobe because it gives space for the ________________.

Hepatic Artery

PARTS OF THE LIVER:

• carries oxygen into the liver

• ~25% of blood supply

Hepatic Portal Vein

PARTS OF THE LIVER:

• carries nutrients to the liver

• ~75% of blood supply

Hepatic Vein

PARTS OF THE LIVER:

• drain deoxygenated blood from the liver into the inferior vena cava

Common Bile Duct

PARTS OF THE LIVER:

• drains bile and biliary excretion products from both lobes into the gallbladder

Liver Lobule

PARTS OF THE LIVER:

• basic anatomical structure of the liver

nephron

The liver lobule’s kidney equivalent is ___________________

Liver/Hepatic Acinus

PARTS OF THE LIVER:

• responsible for hepatic blood flow and metabolic activities

• primary unit of the liver

Glomerulus

The liver/hepatic acinus’ kidney equivalent is ___________________

Portal Triad

PARTS OF THE LIVER:

• consists of hepatic artery, hepatic portal vein, and common bile duct

Sinusoids

PARTS OF THE LIVER:

• large vascular capillaries where the terminal branches of the hepatic artery and portal vein fuse within the liver

drug and nutrient removal

PARTS OF THE LIVER:

Sinusoids

• Facilitates the a.___________________________ before the blood enters the general circulation.

• Lined with endothelial cells of b.______________, which are phagocytic tissue macrophages that are part of the RES or engulf worn-out RBCs and foreign material.

a = ?

Kupffer cells

PARTS OF THE LIVER:

Sinusoids

• Facilitates the a.___________________________ before the blood enters the general circulation.

• Lined with endothelial cells of b.______________, which are phagocytic tissue macrophages that are part of the RES or engulf worn-out RBCs and foreign material.

b = ?

Drug Biotransformation

other name of Drug Metabolism

irreversible conversion

Drug Biotransformation is the ____________________________ of drugs to another substance.

metabolites

In drug biotransformation, the drugs are chemically converted in the body to ______________.

enzymatic

Drug Biotransformation is usually an a.________ process but some drugs are b._______________________________ process.

a = ?

chemically changed by a non-enzymatic

Drug Biotransformation is usually an a.________ process but some drugs are b._______________________________ process.

b = ?

Deativation

POSSIBLE EFFECTS AFTER METABOLISM:

• most drugs undergoes this process as most metabolites become inactive

Activation of Prodrugs

POSSIBLE EFFECTS AFTER METABOLISM:

• pharmacologically inactive compounds designed to maximize the amount of the active species that reaches its site

• in this process, drugs are activated after metabolism

enalapril —> enalaprilate and L-DOPA —> dopamine

POSSIBLE EFFECTS AFTER METABOLISM:

• examples of prodrugs

Active Drugs with Active Metabolites

POSSIBLE EFFECTS AFTER METABOLISM:

• drugs are administered in its active form and is activated again after metabolism

diazepam

POSSIBLE EFFECTS AFTER METABOLISM:

• example of active drugs with active metabolites

Active Drugs with Toxic Metabolites

POSSIBLE EFFECTS AFTER METABOLISM:

• usually experienced when high doses of drugs are administered, which saturates the enzymes and causes toxic metabolites to be synthesized

Acetaminophen

POSSIBLE EFFECTS AFTER METABOLISM:

• example of active drugs with toxic metabolites

Glucuronidation and Sulfation

POSSIBLE EFFECTS AFTER METABOLISM:

Active Drugs with Toxic Metabolites

1. At normal/therapeutic doses: Acetaminophen undergoes a.____________ metabolism, which is the desired mode of metabolism, but the enzymes needed for these metabolism processes are saturable.

2. When these enzymes are fully saturated: Acetaminophen will undergo b._______ enzyme metabolism and produce c._______, a toxic metabolite.

3. This toxic metabolite can be conjugated by d.___________, but this enzyme is also saturable.

4. When this enzyme is fully saturated, it will stop converting the toxic metabolite to e.___________________.

5. It will go back to producing the toxic metabolite via f._________________.

6. This toxic metabolite can bind to liver cells and produce g._____________.

a = ?

CYP-450

POSSIBLE EFFECTS AFTER METABOLISM:

Active Drugs with Toxic Metabolites

1. At normal/therapeutic doses: Acetaminophen undergoes a.____________ metabolism, which is the desired mode of metabolism, but the enzymes needed for these metabolism processes are saturable.

2. When these enzymes are fully saturated: Acetaminophen will undergo b._______ enzyme metabolism and produce c._______, a toxic metabolite.

3. This toxic metabolite can be conjugated by d.___________, but this enzyme is also saturable.

4. When this enzyme is fully saturated, it will stop converting the toxic metabolite to e.___________________.

5. It will go back to producing the toxic metabolite via f._________________.

6. This toxic metabolite can bind to liver cells and produce g._____________.

b = ?

NAP-QI

POSSIBLE EFFECTS AFTER METABOLISM:

Active Drugs with Toxic Metabolites

1. At normal/therapeutic doses: Acetaminophen undergoes a.____________ metabolism, which is the desired mode of metabolism, but the enzymes needed for these metabolism processes are saturable.

2. When these enzymes are fully saturated: Acetaminophen will undergo b._______ enzyme metabolism and produce c._______, a toxic metabolite.

3. This toxic metabolite can be conjugated by d.___________, but this enzyme is also saturable.

4. When this enzyme is fully saturated, it will stop converting the toxic metabolite to e.___________________.

5. It will go back to producing the toxic metabolite via f._________________.

6. This toxic metabolite can bind to liver cells and produce g._____________.

c = ?

glutathione

POSSIBLE EFFECTS AFTER METABOLISM:

Active Drugs with Toxic Metabolites

1. At normal/therapeutic doses: Acetaminophen undergoes a.____________ metabolism, which is the desired mode of metabolism, but the enzymes needed for these metabolism processes are saturable.

2. When these enzymes are fully saturated: Acetaminophen will undergo b._______ enzyme metabolism and produce c._______, a toxic metabolite.

3. This toxic metabolite can be conjugated by d.___________, but this enzyme is also saturable.

4. When this enzyme is fully saturated, it will stop converting the toxic metabolite to e.___________________.

5. It will go back to producing the toxic metabolite via f._________________.

6. This toxic metabolite can bind to liver cells and produce g._____________.

d = ?

3-(N-Acetyl-L-cystein-S-yl) Acetaminophen

POSSIBLE EFFECTS AFTER METABOLISM:

Active Drugs with Toxic Metabolites

1. At normal/therapeutic doses: Acetaminophen undergoes a.____________ metabolism, which is the desired mode of metabolism, but the enzymes needed for these metabolism processes are saturable.

2. When these enzymes are fully saturated: Acetaminophen will undergo b._______ enzyme metabolism and produce c._______, a toxic metabolite.

3. This toxic metabolite can be conjugated by d.___________, but this enzyme is also saturable.

4. When this enzyme is fully saturated, it will stop converting the toxic metabolite to e.___________________.

5. It will go back to producing the toxic metabolite via f._________________.

6. This toxic metabolite can bind to liver cells and produce g._____________.

e = ?

CYP-450 metabolism

POSSIBLE EFFECTS AFTER METABOLISM:

Active Drugs with Toxic Metabolites

1. At normal/therapeutic doses: Acetaminophen undergoes a.____________ metabolism, which is the desired mode of metabolism, but the enzymes needed for these metabolism processes are saturable.

2. When these enzymes are fully saturated: Acetaminophen will undergo b._______ enzyme metabolism and produce c._______, a toxic metabolite.

3. This toxic metabolite can be conjugated by d.___________, but this enzyme is also saturable.

4. When this enzyme is fully saturated, it will stop converting the toxic metabolite to e.___________________.

5. It will go back to producing the toxic metabolite via f._________________.

6. This toxic metabolite can bind to liver cells and produce g._____________.

f = ?

hepatotoxicity

POSSIBLE EFFECTS AFTER METABOLISM:

Active Drugs with Toxic Metabolites

1. At normal/therapeutic doses: Acetaminophen undergoes a.____________ metabolism, which is the desired mode of metabolism, but the enzymes needed for these metabolism processes are saturable.

2. When these enzymes are fully saturated: Acetaminophen will undergo b._______ enzyme metabolism and produce c._______, a toxic metabolite.

3. This toxic metabolite can be conjugated by d.___________, but this enzyme is also saturable.

4. When this enzyme is fully saturated, it will stop converting the toxic metabolite to e.___________________.

5. It will go back to producing the toxic metabolite via f._________________.

6. This toxic metabolite can bind to liver cells and produce g._____________.

g = ?

Mixed-Function Oxidases

hepatic enzymes that are responsible for oxidation and reduction of drugs (xenobiotics), and certain natural metabolites (ie. steroids)

parenchymal cells

Mixed-Function Oxidases are contained in the a._____________________ of the liver in association with the b._________________________, which is a network of lipoprotein membranes within the cytoplasm and continuous with the cellular and nuclear membranes.

a = ?

endoplasmic reticulum

Mixed-Function Oxidases are contained in the a._____________________ of the liver in association with the b._________________________, which is a network of lipoprotein membranes within the cytoplasm and continuous with the cellular and nuclear membranes.

b = ?

Asynthetic reactions, oxidation, reduction, and hydrolysis

PATHWAYS OF DRUG BIOTRANSFORMATION:

• Phase I metabolism includes:

functionalization

PATHWAYS OF DRUG BIOTRANSFORMATION:

• Phase I metabolism is _____________________

conjugations

PATHWAYS OF DRUG BIOTRANSFORMATION:

• Phase II metabolism is _____________________

more polar

PATHWAYS OF DRUG BIOTRANSFORMATION:

• Phase I metabolism makes the drug _______________, to increase excretion in the urine.

more ionized

PATHWAYS OF DRUG BIOTRANSFORMATION:

• Phase II metabolism makes the drug ______________________

Oxidation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• addition of oxygen or negatively charged radical

• removal of hydrogen or positively charged radical

CYP enzymes or Alcohol Dehydrogenase

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Oxidation uses ____________________________

most common

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Oxidation is the _______________ Phase I metabolism.

Alcohol Dehydrogenase

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Oxidation Enzymes: oxidation by removal of hydrogen

Aldehyde Dehydrogenase

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Oxidation Enzymes: oxidation by addition of oxygen

Acetaldehyde

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Oxidation: toxic metabolite; primary cause of intoxication by too much alcohol

Carboxylic Acid

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Oxidation: polar product for excretion

Aromatic Hydroxylation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• addition of hydroxyl group (-OH) to an aromatic ring

CYP 2C9

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Aromatic Hydroxylation is metabolized by ____________

Oxidative Dealkylation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• removal of an alkyl group

CYP2D6

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Oxidative Dealkylation uses ___________

Reduction

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• addition of hydrogen or positively charged radical

• removal of oxygen or negatively charged radical

anaerobic

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Reduction requires a.________ conditions and uses b._________

a = ?

reductases

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Reduction requires a.________ conditions and uses b._________

b = ?

Nitro Reduction

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• converting nitro group to amine group

Carbonyl Reduction

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• converting ketones/aldehydes to a more polar alcohol

Hydrolysis

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• drug is split by combining with water molecule

• forms a variety of polar functionality (esters and amides) susceptible for Phase II metabolism

esterases and amidases

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

• Hydrolysis is carried out by hydrolytic enzymes such as ______________

Glucuronidation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• most dominant conjugative pathway

• uses Glucuronic Acid as its conjugating agent

Uridine diphosphoglucuronic acid

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• high-energy intermediate of glucuronidation

Glycine Conjugation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• uses glycine as its conjugating agent

Coenzyme A thioesters

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• high-energy intermediate of glycine conjugation

Glutamine Conjugation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• conjugation with coenzyme A (CoA) followed by conjugation with amino acids (Taurine and Glutamine)

• uses glutamine as its conjugating agent

Sulfation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• uses sulfotransferases (SULTs)

• for phenols/alcohols

Methylation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• drugs and xenobiotics can undergo O-, N-, and S- methylation catalyzed by methyltransferases

• transfers methyl to make drugs more HIPE

Acetylation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• the acetylated product (addition of an acyl group) is usually less polar than the parent drug

• less polar metabolite can be reabsorbed in the renal tubule and has a longer elimination half-life

• N-acetyltransferase enzyme responsible for catalyzing the acetylation of hydralazine, isoniazid, procainamide, and other drugs demonstrates a genetic polymorphism

Slow Inactivators

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II — Acetylation

• metabolized slowly, which leads to accumulation and toxicity

Caucasians

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II — Acetylation

• Slow Inactivators are common in ___________________

Rapid Inactivators

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II — Acetylation

• metabolizes quickly, which causes plasma concentration to not reach MEC

Asians

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II — Acetylation

• Rapid Inactivators are common in:

Glutathione Conjugation

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

• tripeptide of glutamic acid-cysteine-glycine

• important in the detoxification of reactive oxygen intermediates into nonreactive metabolites

mercaptopuric acid

GLUTATHIONE

1. The resulting GSH conjugates are precursors for ____________________ which is a N-acetylcysteine metabolites.

2. The enzymatic formation of GSH conjugates is _____________.

3. _______________________ may deplete GSH in the cell.

4. Antidote for APAP poisoning is _______________________, a drug molecule that contains available sulfhydryl (R-SH) groups

1 = ?

saturable

GLUTATHIONE

1. The resulting GSH conjugates are precursors for ____________________ which is a N-acetylcysteine metabolites.

2. The enzymatic formation of GSH conjugates is _____________.

3. _______________________ may deplete GSH in the cell.

4. Antidote for APAP poisoning is _______________________, a drug molecule that contains available sulfhydryl (R-SH) groups

2 = ?

high doses of APAP

GLUTATHIONE

1. The resulting GSH conjugates are precursors for ____________________ which is a N-acetylcysteine metabolites.

2. The enzymatic formation of GSH conjugates is _____________.

3. _______________________ may deplete GSH in the cell.

4. Antidote for APAP poisoning is _______________________, a drug molecule that contains available sulfhydryl (R-SH) groups

3 = ?

N-acetylcysteine

GLUTATHIONE

1. The resulting GSH conjugates are precursors for ____________________ which is a N-acetylcysteine metabolites.

2. The enzymatic formation of GSH conjugates is _____________.

3. _______________________ may deplete GSH in the cell.

4. Antidote for APAP poisoning is _______________________, a drug molecule that contains available sulfhydryl (R-SH) groups

4 = ?

Mixed-Function Oxidases

ENZYMES IN DRUG BIOTRANSFORMATION:

• monoxygenase enzymes

• responsible for redox of drugs and natural metabolites

CYP Isoenzymes (CYP 450)

ENZYMES IN DRUG BIOTRANSFORMATION

• group of heme containing enzymes which is responsible for phase 1 reactions

• catalyzes the biotransformation of various endogenous compounds such as steroids

• located in other tissues (kidney, GI tract, skin, and lung)

Monoamine Oxidase

ENZYMES IN DRUG BIOTRANSFORMATION

• deaminates endogenous substrates including NT (dopamine, serotonin, norepinephrine, and epinephrine)

Alcohol and Aldehyde Dehydrogenase

ENZYMES IN DRUG BIOTRANSFORMATION:

• found in the soluble fraction of liver

• involved in the metabolism of ethanol

Xanthine Oxidase

ENZYMES IN DRUG BIOTRANSFORMATION

• converts hypoxanthine —> xanthine —> uric acid

UDP Glucuronic Acid (UDPGA)

Type of Conjugation: Glucuronidation

Endogenous Reactant: ?

Transferase Enzyme:

UDP glucoronosyl-transferase

Type of Conjugation: Glucuronidation

Endogenous Reactant:

Transferase Enzyme: ?