The LADMER System: Metabolism

Drug Metabolism

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

Liver

Principal/Main site of metabolism

●Lung - for inhalation/volatile gases

●Skin

●Gastrointestinal mucosal cells

●Microbiological flora in the distal portion (part na nagb-biotransform) of the ileum

●Large intestine

●Kidneys

Other/Minor sites of metabolism

True

T or F

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

First-Order Elimination

The metabolism rate constant (km) is the sum of the rate constants for the formation of each metabolite.

Rate Constant (k)

rate constant of elimination

kR or ke

first-order rate constant for excretion

kNR or km

first-order rate constant for metabolism

○ METABOLISM (Biotransformation)

○ EXCRETION (Renal)

How are drugs removed from the body?

Liver

-Major organ responsible for drug metabolism

-Both a synthesizing and an excreting organ

Liver lobule

-Basic anatomical unit

-contains parenchymal

cells in a network of interconnected lymph and blood

vessels

hepatic artery

carries oxygen into the liver (~25% of blood supply)

Hepatic Portal Vein

Carries nutrients to the liver (~75% of blood supply)

Hepatic Vein

Drains deoxygenated blood from the liver into the IVC (inferior vena cava)

Common Bile Duct

Drains bile and biliary excretion products from both lobes into the gallbladder

Sinusoids

-Large vascular capillaries where the terminal branches of the hepatic artery and portal vein fuse within the liver

-Facilitates drug and nutrient removal before the blood enters the general circulation

Sinusoids

Lined with endothelial cells of Kupffer cells (phagocytic tissue macrophages that are part of the RES (Reticuloendothelial System); engulf worn-out RBCs and foreign material)

flow and site

Drug metabolism in the liver has been shown to be ____________ dependent

-Hepatic diseases

-genetic differences in enzyme levels

-environmental factors

What can affect half-lives of drugs eliminated by drug metabolism

Drug Biotransformation

-Drugs are chemically converted in the body to metabolites

-Usually an enzymatic process

1. Deactivation

2. Activation (Prodrugs)

3. Active drugs with active metabolites

4. Active drugs with toxic metabolites

POSSIBLE EFFECTS AFTER METABOLISM:

Prodrugs

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

Enalapril

antihypertensive (ACEi)

Dopamine

for Parkinson's Disease

Diazepam

Long-acting sedative used for muscle spasms.

Demethylation

Metabolic process converting Diazepam to Desmethyldiazepam.

Hydroxylation

Conversion of Desmethyldiazepam to Oxazepam.

Active Metabolites

Metabolites that retain pharmacological activity.

Toxic Metabolites

Harmful metabolites produced during drug metabolism.

First-Pass Effect

Reduction of drug concentration before systemic circulation.

Drug metabolism

Conversion to a more excretable form (more water-soluble form)

NAPQI

Toxic metabolite causing liver damage if there's not enough GSH in the liver

Mixed-function oxidases (MFOs)

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

MFOs are contained in the parenchymal cells of the liver in association with the endoplasmic reticulum (a network of lipoprotein membranes within the cytoplasm and continuous with the cellular and nuclear membranes)

MFOs are contained in the ______ of the liver in association with the _______ (a network of lipoprotein membranes within the cytoplasm and continuous with the cellular and nuclear membranes)

converts lipophilic substance -> hydrophilic

Main mechanism (MFOs)

Phase I

-mostly REDOX & hydrolysis reactions

● Asynthetic reactions

● Oxidation

● Reduction

● Hydrolysis

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase I

● Synthetic reactions

● Conjugations

PATHWAYS OF DRUG BIOTRANSFORMATION:

Phase II

Phase II

-Conjugation reactions

-To make drug more ionized (and readily excretable)

Phase I

-Functionalization

-To make drug more polar, to increase excretion in urine

CYP450

-known metabolic enzyme identified by 450nm wavelength

-has a lot of cytochrome isozymes

Phenylbutazone

mostly used for rheumatoid arthritis;

not commonly used since it has a lot of ADRs

CYP3A4

most abundant in the liver; causes first-pass effect

CYP2E1

for alcohol metabolism

False

IV drug will not undergo Phase I and Phase II; straight to elimination

T or F

IV drug will undergo Phase I and Phase II; straight to elimination

PHASE I - OXIDATION

-Addition of Oxygen or negatively charged radical

-Removal of Hydrogen or positively charged radical

PHASE I - OXIDATION

What Phase?

-AROMATIC HYDROXYLATION

-OXIDATIVE DEALKYLATION

Phase 1 - Reduction

Phase 1 Reaction:

-Addition of Hydrogen or positively charged radical

-Removal of Oxygen or negatively charged radical

Methylation

Phase II reaction adding methyl groups to drugs.

Acetylation

Phase II reaction removing carbonyl groups from drugs.

Phase 1 - Hydrolysis

Phase I reaction:

-drug is split combining with water molecule

-carried out by hydrolytic enzymes

forms a variety of polar functionality susceptible for

Phase II metabolism

PHASE II - GLUCURONIDATION

Phase 2 Reaction:

-Most dominant conjugative pathway

-Conjugating agent: Glucuronic acid

Uridine diphosphoglucuronic acid (UDPGA)

High-energy intermediate in Phase II Glucuronidation

Glycine;

Coenzyme A thioesters

PHASE II - GLYCINE CONJUGATION

-Conjugating agent ____

-High-energy intermediate: ____

PHASE II - GLUTAMINE CONJUGATION

Phase II reaction:

-Conjugation with coenzyme A (CoA) followed by conjugation with amino acids such as taurine and glutamine.

Sulfotransferases (SULTs)

Conjugating agent in PHASE II - SULFATION

PHASE II - METHYLATION

In humans, drugs and xenobiotics can undergo O-, N-, and S- methylation catalyzed by methyltransferases.

PHASE II - ACETYLATION

-The acetylated product is usually less polar than the parent drug.

-The 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 (for hypertension), isoniazid (anti-TB), procainamide, and other drugs demonstrates a genetic polymorphism

-"Slow inactivators" and "rapid inactivators"

Glutathione (GSH)

-a tripeptide glutamic acid-cysteine-glycine.

-important in the detoxification of reactive oxygen intermediates into nonreactive metabolites.

N-acetylcysteine

-Antidote for APAP poisoning

-a drug molecule that contains available sulfhydryl (R-SH) groups.

Mixed-Function Oxidases (MFOs)

-Monooxygenase enzymes

-Responsible for redox of drugs and natural

metabolites

CYP isoenzymes

-Catalyzes the biotransformation of various

endogenous compounds (Steroids)

-Located in other tissues - kidney, GI tract, skin,

lung

Reactive Oxygen Species (ROS)

Chemicals causing advanced aging.

CYP2D6

Human isozyme that metabolizes antidepressant drugs

CYP2C9

Responsible for warfarin metabolism in humans.

CYP2C19

Metabolizes proton pump inhibitors (PPIs) like '-prazoles'.

CYP1A2

Metabolizes methylxanthines such as caffeine.

CYP3A4

Most abundant CYP enzyme in the liver, causes first-pass effect

CYP2E1

Isozyme for alcohol metabolism

Alcohol- and Aldehyde- dehydrogenase

-Found in the soluble fraction of liver

-Involved in metabolism of ethanol

Xanthine oxidase

Converts hypoxanthine xanthine to to uric acid in metabolism.

Xanthine oxidase inhibitors

Lower serum uric acid; used for gout treatment (anti-gout)

Enzyme inhibitors

drug/chemical that reduces enzyme activity

Reversible inhibition

increasing the dose of the second drug taken can displace the first drug that was administered.

Competitive inhibition

Inhibitor competes for the same enzyme binding site; mechanism is direct and is rapidly reversible

Noncompetitive inhibition

Inhibitor and substrate do not compete for the same active site, because of an allosteric site.

Irreversible inhibition

permanent inhibition of the enzyme

First-pass effect

A phenomenon where a portion of the orally administered drug undergoes elimination before it has a chance to be absorbed into systemic circulation.

First-pass effect

Presystemic Elimination

Enzyme inducers

drug/chemical that increases enzyme

activity by transcriptional activation leading to increased synthesis of more CYP enzyme proteins.

Intrinsic clearance

-The ability of the liver to remove drug independently of blood flow

-Primarily due to the inherent ability of biotransformation enzymes to metabolize drug as it enter the liver

-Presence of other drugs

-Presence of environmental condition

Intrinsic clearance depends on:

Fractional difference

the extent to which an orally administered dose undergoes first-pass effect

1. The entire drug dose administered orally is released from dosage form and is made available for absorption,

2. The drug is not acid-labile

3. The drug is not destroyed in the GIT by the GI enzymes

4. The AUCoral < AUCIV

What conditions must be met, in order for a drug to undergo first-pass effect?

Increased drug effect

Higher plasma concentration leading to stronger effects.

False

Drugs with Fractional difference > 0.9 are best administered by routes other than those involving the GIT

T or F

Drugs with Fractional difference < 0.9 are best administered by routes other than those involving the GIT

Hepatic clearance

-Volume of drug-containing plasma that is cleared of the drug by liver per unit

-Includes excretion of drug into the bile

-Drugs with relatively high MW (>500)

-Polar drugs

-Glucuronide conjugates of various drugs

Biliary excretion involves:

Hepatic Extraction Ratio

-The fraction of the drug removed from plasma by the live

-Amount of drug removed from plasma by the liver

Hepatic Blood Flow (QH)

Rate of blood flow through the liver.

INCREASED QH, INCREASED rate of removal of drug by the liver

INCREASED QH, _____ rate of removal of drug by the liver

DECREASED QH, DECREASED rate of removal of drug by the liver

_____ QH, DECREASED rate of removal of drug by the liver

~1.5 L/min.

hepatic blood flow under normal conditions: ___

○ Presence of drugs (Example: Propranolol)

○ Presence of disease state

○ Exercise

Hepatic blood flow may be affected by:

Enterohepatic Circulation

-Reabsorption of the drug after hepatic pass

-Recycling of drug

CA

the arterial concentration of drug in plasma entering the liver

CV

the venous concentration of drug in plasma exiting the liver

may range from 0 to 1

Hepatic Extraction Ratio Range

HER < 0.2 indicates low drug removal.

Low Hepatic Extraction Ratio