Metabolism and Elimination

What 2 types of compounds are poorly excreted in urine?

Lipophilic and unionized

How does metabolism usually alter compounds?

More hydrophilic or less lipophilic to make elimination easier

Wat are the 2 types of metabolism pathways?

Phase 1 (metabolic)

Phase 2 (conjugation)

What are examples of metabolic reacitons?

Oxidation, reduction, hydrolysis

What is the net effect of metabolic reactions?

Increased hydrophilicity or decreased lipophilicity

What are products of phase 1 reactions used for?

Excretion or provide functional groups for phase 2 reactions

What happens to cefovecin after IV dosing?

Blood flows to the liver

Low affinity for hepatic metabolizing enzymes so most of the drug passes through unmetabolized

Low affinity for drug transporters in the liver so little drug is secreted in bile

Most leaves the liver intact

What happens to morphine in the liver?

High affinity for Phase II hepatic metabolizing enzymes causing most of the drug to be metabolized and inactivated

Low affinity for drug transporters in liver causes a small amount to be secreted in bile

Most drug leaves the liver as an inactive metabolite

What is the Cytochrome P450 (CYP) Mixed-Function Oxidase MFO system?

It is a primary enzyme family for drug metabolism (phase 1)

Where is the CYP Mixed-Function Oxidase system mostly located?

Liver mostly also intestines, kidneys, skin

What is the rate limiting step in the metabolic pathway?

Cytochrome P450 enzyme

What is the difference between CYP isoforms?

Minor structural variations but a large impact on specificity

What are the isoforms of CYP?

CYP 1A, CYP 2B, CYP 2E, CYP 2C, CYP 2D, CYP 3A

What is the result of having many different CYP isoforms?

Different CYP specificities for substrates, inducers, and inhibitors

What CYP metabolizes medthadone?

CYP2B11 in dogs

What does Ketoconazole do in dogs?

It INHIBITS CYP3A12

What does fluconazole do?

It inhibits CYP2B11

What happens if you give methadone and fluconazole in dogs?

Fluconazole will inhibit the enzyme the metabolizes methadone causing a stronger amount of methadone that gets past the liver

What can you do to increase metabolism?

Increase synthesis of CYP

Decrease degradation of CYP

Activation of pre-existing CYP components

What can you do to decrease metabolism?

Reversible inhibition of CYP

Destruction of CYP

Inhibiting CYP synthesis

What is unique about phenobarbital and CYP?

It is a CYP2B11 inducer and a substrate so it increases its own metabolism over time. This means that if you give phenobarbital treatment every day the concentration will be much lower than anticipated

Ketamine is a substrate of what CYP?

CYP2B11

What are examples of phase 2 or conjugation reactions?

Addition of a polar endogenous substance to the drug or metabolite

A functional group must be present

Products of what phase of metabolism are larger or more polar?

phase 2

What happens to metabolites after phase 2?

Excretion in bile, urine, feces

What are the main types of phase 2 conjugation reactions?

Glucoronidation

Acetylation

Sulfate conjugation

Amino acid conjugation

What is glucuronidation?

Drug substance and glucuronic acid reactions

What are some species differences in glucuronidation?

Cats are deficient in some glucuronide conjugation enzyme

Why are cats subject to acetaminophen toxicity?

They lack the enzymes for glucuronide conjugation and cant excrete CYP metabolites which are toxic

What is a species difference for acetylation?

Dogs are deficient at acetylation

What does canine deficiency in acytlation cause in dogs?

Increase toxicity risk of sulfonamide antimicrobials

What does sulfonamide toxicity in dogs cause?

Hepatotoxicity, polyarythropathy, blood dyscrasias, death

What is sulfate conjugation?

Substrate and phosphoadenosyl phosphosulfate

What is a species difference in sulfate conjugation?

Swine are deficient

Cats use this to eliminate morphine because they are deficient in glucuronic conjugation

What is amino acid conjugation?

You add an amino acid (usually glycine) to a substrate

What is a species difference in amino acid conjugation?>

Avian species are deficient

Benzoic acid is metabolized to hippuric acid by glycine conjugation

What is biliary secretion?

It is a carrier mediated way to expunge large molecular weight drugs and metabolites

Why does carrier mediated matter for biliary secretion?

It is subject to saturation, competition and specificity

What is biliary secretion useful for?

More polar drugs that are poorly eliminated in urine

What drug is primarily removed from the body with biliary secretion?

Doxycycline

What is a specific transporter for biliary secretion?

P-glycoprotein

What are 3 ways for hepatic drug metabolism or elimination?

Phase 1 metabolism (CYP)

Phase 2 metabolism

Biliary secretion

T/F hepatic drug metabolism/elimination is highly specific?

True

What are the steps enterohepatic recycling?

Bile duct empties into duodenum containing the drug metabolite

Intestinal bacterial flora will de-conjugate some drugs and it can be reabsorbed

What is unique about the metabolism of codeine in dogs?

It undergoes phase 1 then phase 2 metabolism and also just phase 2 metabolism

Learn the codeine metabolism picture

Will do

What is the net effect of enterohepatic recycling?

A single drug molecule is secreted and absorbed several times increasing drug exposure

What happens if a drug is tightly bound to a plasma protein when it gets to the kidney?

Very little drug will pass through the glomerulus

Why would you do multiple doses of activated charcoal for some toxicities?

It helps combat enterohepatic recycling

Renal drug elimination is determined by waht?

Glomerular filtration

Tubular secretion

Tubular reabsorption

Describe the metabolism of tramadol

Tramadol is demethylated into n-desmethyltramadol then excreted in the urine

Phase 1 only

What happens to the pharmacologic activity when a drug is metabolized?

It usually decreases

What is a pro-drug?

Inactive drug is metabolized to the active form

What is an example of a pro-drug?

Enalapril - metabolized to enalaprilat and then is more active

What is lethal synthesis?

Dru is converted to a toxic metabolite

What are two examples of lethal synthesis?

Acetaminophen (cats)

Ethylene glycol

Give an example of a drug that the metabolite is more active

Tramadol: metabolized to o-desmethyltramadol 200x analgesic activity in cats

How to you treat ethylene glycol toxicity and why?

Ethanol because it saturates alcohol DH and will prevent ethylene glycol from being converted into a lethal molecule

Where does extrahepatic metabolism occur?

GI tract, skin, kidneys, spleen, lung

Describe the ratio of where morphine is metabolized in dogs

50% in the liver

50% in the intestines (extrahepatic metabolism)

What is the clinical consequence of dogs metabolizing morphine in the liver and intestines?

Profound liver disease only decreases morphine elimination by 50% in dogs

Why does it matter that active tubular secretion is carrier mediated?

Drugs will be secreted relative to its affinity to plasma proteins or the transporter b

What drug is secreted into the kidneys by the acid transporter OAT3?

Penicillin

What drug is secreted into the kidneys by the base transporter OCT2?

Trimethoprim

What is the significance of active tubular secretion getting saturated?

You can introduce a competitor to the transporter to keep more of the drug in the blood stream

Used when there was a penicillin shortage with probenecid competing

What is special about the glomerular epithelium?

It is charged so it makes charged compounds harder to filter through

T/F glomerular filtration is saturable?

False

GFR is dependent on what 3 things?

Renal blood pressure

plasma oncotic pressure

Number of glomeruli

What is required for a drug to be reabsorbed in the proximal and distal renal tubules?

Must be lipophilic and unionized

Alkaline urine will favor excretion of what?

Weak acids

Acidic urine will favor excretion of what?

Weak bases

Learn the formula for renal elimination

OK

T/F there are phase 1 and phase 2 metabolism in the kidney?

True

Why is cilastatin given with imipenem?

Cilastatin will inhibit brush border metabolism to allow for imipenem to remain effective in the urinary tract and clear a UTI

What drugs undergo pinocytosis in the kidney?

Aminoglycosides

What does pinocytosis cause?

Some of the drug is stored in the kidney. This causes nephrotoxicity