Pharm 5: ADME/Pharmacokinetics Part 3: Metabolism and Elimination

Renal excretion (urine), hepatic elimination (bile, feces)

Drugs are eliminated from the body primarily by ___ or ___.

Lipid-soluble, active, protein-bound

For a drug to be pharmacologically active, it must be sufficiently ___ to be absorbed across cellular membranes and distributed in a biologically ___ form (e.g., not ___) to the receptor site.

Polar, water-soluble

For the drug to be eliminated from the body, it is usually metabolized to ___, ___ products, which can be excreted by the kidney or in the bile.

Lipid-soluble, active, water-soluble, inactive

The process of drug metabolism usually converts a ___, pharmacologically ___ drug to a ___, pharmacologically ___ metabolite.

Pro-drug

When a drug that is initially inactive is metabolized to an active form, the inactive form is referred to as a ___.

Phase I metabolism

1. Metabolic reactions which add polar groups (e.g., –OH, –COOH) or remove non-polar groups

   1. These metabolites are either:

      1. Directly excreted by biliary or renal processes

      2. Provide functional groups to which conjugates may be added in phase II metabolic reactions

Oxidation, reduction, hydrolysis

Major phase I metabolic reactions

Conjugation

Reaction type of phase II metabolism

Phase II metabolism

A functional group (e.g., –OH, –COOH, –NH₂) on a drug or phase I metabolite is combined with an activated endogenous substrate (glucuronic acid, glutathione, acetic acid, sulfate, glycine, etc.) to form a more polar, water-soluble conjugated compound

Phase I

Which phase of metabolism?:

Product has increased water solubility and may be pharmacologically inactive, less active, or more active

Phase II

Which phase of metabolism?:

Product has significantly increased water solubility and significantly decreased biologic activity

Oxidation

Additional of oxygen or removal of a hydrogen from the drug

Microsomal, non-microsomal

Types of oxidation

Microsomal oxidation

Which type of oxidation includes the cytochrome P-450 family of enzymes and mixed function oxidase?

Non-microsomal oxidation

Which type of oxidation involves a few chemicals being oxidized by enzymes found in the cytosol and mitochondria?:

• Alcohol dehydrogenase

• Aldehyde dehydrogenase

• Monoamine oxidase

• Xanthine oxidase

Reduction

Addition of hydrogen to the drug molecule; both microsomal and non-microsomal enzymes are involved

Hydrolysis

Addition of water molecule to the drug

1. Esterases (e.g., procaine, acetylcholine)

2. Amidases (e.g., procainamide)

Form a polar, water-soluble conjugated compound

Main goal of phase II metabolism

Microsomes, mitochondria, cytosol

Where are Phase II enzymes located?

Water solubility, biological activity, kidney

Conjugated products have much greater ___, relatively no ___, and are more readily excreted by the ___.

Glucuronyl transferases

Cats have low ___.

Acetyltransferases

Dogs have low ___.

Sulfate conjugation

Pigs have low levels of enzymes necessary for ___.

Saturated

In cats, sulfate-conjugating systems are easily ___.

1. Glucuronidation (e.g., morphine, aspirin, acetaminophen, ethanol)

2. Acetylation (e.g., sulfonamides)

3. Glutathione conjugation (e.g., ethacrynic acid, acetaminophen)

4. Glycine conjugation (e.g., salicylic acid)

5. Sulfate conjugation (e.g., acetaminophen)

6. Methylation (e.g., catecholamines)

Phase II metabolism reactions

Glucuronidation

Which phase II reaction?:
Location: ER

Endogenous substrates: Steroids, thyroxine, catecholamines, bilirubin

Sulfation

Which phase II reaction?:

Location: Cytosol

Endogenous substrates: Steroids, carbs

Acetylation

Which phase II reaction?:

Location: Cytosol

Endogenous substrate: Serotonin

Methylation

Which phase II reaction?:

Locations: Cytosol, ER

Endogenous substrates: Biogenic amines

Glutathione conjugation

Which phase II reaction?:

Locations: Cytosol and ER

Endogenous substrates: Metabolites of arachidonic acid

Propofol

Greyhounds have decreased metabolism of ___.

Celecoxib

Beagles have decreased metabolism of ___.

Azathioprine

Labradors have decreased metabolism of ___.

Acepromazine

Boxers have decreased metabolism of ___.

Young animals

Which animals in the population may have low levels of Phase I and Phase II enzymes?

Urine

Major route of drug excretion

Urine (major route)

1. Glomerular filtration (unbound drugs) to get drug in urine

2. Active tubular secretion (organic acid and base transporters in the proximal tubule) to get drug in urine

3. Passive tubular reabsorption (lipid-soluble drugs) to put drug back in body

   1. Can “ion-trap” weak acids and bases in urine/bladder

Bile and feces

1. Active transport for acidic, basic, and neutral drugs

2. Enterohepatic circulation

Enterohepatic circulation

1.  Glucuronide-conjugated metabolites excreted in bile

   1. Bacterial beta-glucuronidases in intestine cleave biliary excreted Ph. II conjugates, allowing reabsorption from intestine into portal vein and back to liver

Breast milk

Weak bases are highly concentrated in milk, which is more acidic than plasma —> ion trapping