4 – Metabolism Flashcards
Biotransformation
- The lipophilic nature of drugs that allow them to diffuse across cell membranes is also a HINDRANCE to their elimination from the body
o *it’s essential to biotransformation drugs to more water-soluble metabolites - Main determinant of a drugs half-life
Biotransformation enzymes
- Convert lipophilic drugs into highly water-soluble metabolites that are easily excreted from the body
Categorization of biotransformation reactions
-phase 1
-phase 2
Phase 1
o Enzymes modify drugs mainly by OXIDATION
Ex. add an hydroxyl group
o Cytochrome P450-dependent monooxygenases (CYPs)
Phase 2
o CONJUGATE the drug with a high polar endogenous compound in the cell
Ex. CHO, sulphate, acetate
Sites of drug biotransformation
- Liver: high (MOST IMPORTANT)
- Lung, kidney, intestine: medium
- Skin, testes, placenta, adrenals: low
- NS: very low
Cytochrome P450-dependent monooxygenases (CYPs)
- Add or expose a polar functional group to lipophilic drug molecule
- Located on smooth endoplasmic reticulum
- Monooxygenase: catalyze the insertion of an oxygen atom
- *also involved in a wide variety of catabolic and anabolic reactions involving endogenous compounds (ex. steroid hormones)
- *usually INACTIVATE and drug, but sometimes can BIOACTIVATE a drug
Cytochrome P450-dependent monooxygenases (CYPs): BROAD
o One enzyme can bio transform many drugs
Cytochrome P450-dependent monooxygenases (CYPs): OVERLAPPING
o One drug can be biotransformed by several enzymes
Hepatic portal venous system
- Delivers all substances absorbed from the gut to the liver BEFORE they reach systemic circulation
“First-pass effect”
- Can result in nearly complete INACTIVATION (>90%) of certain drugs after oral ingestion
o Why certain drugs are NOT given orally
Intravenous administration will bypass the ‘first-pass effect’
Oral bioavailability
- Fraction of an orally administered drug that reaches the systemic circulation in an unchanged form
- Bioavailability = area under the curve oral / area under the curve IV
Phase 2: examples
- Glucuronidation
- Sulfation
- Acetylation
- Glucuronidation
o Enzyme: UDP-glucuronosyl transferase (UDP-GT or UGT)
o Cofactor: UDP-glucuronic acid
o Location: smooth ER membrane
Probably why it is a major phase II enzyme as it is located by CYP
o *cats can’t do it
Ex. don’t give them acetaminophen
- Sulfation
o Enzyme: sulfotransferase (ST)
o Cofactor: PAPS
o *pigs are poor sulfators
Glutathione conjugation
- One of our most important defenses against electrophiles (ex. ROS and epoxides)
- Enzyme: Glutathione S-transferase (GST)
o Abundant
o Approximately 5% of cytosolic protein in liver cells - Cofactor: Glutathione (GSH)
o mM concentrations in most cells (LARGE) - *THIS IS YOUR BESTY
- Acetylation
o Enzyme: N-acetyltransferase (NAT)
o Cofactor: acetyl coenzyme A
o *dogs are poor acetylators
Genetic and environmental factors influencing biotransformation
- Enzyme induction and inhibition
- Intraspecific differences
- Interspecific differences
- Sex and age
- Diet (nutritional factors)
- Disease (underlying pathology)
Enzyme induction and inhibition
- CYP enzymes and phase 2 enzymes
- Very clinically relevant w/respect to duration of drug action and drug interactions
- Depletion of cofactors (ex. glutathione) can be important
‘suicide’ inhibition
- Kills the enzymes(will NEVER work again)
Intraspecies differences
- Genetic differences in expression of enzymes
- Can result in subset of population being ‘poor metabolizers’ or even ‘rapid metabolizes
o Ex. rapid=need to give more of a drug to get a response - Ex. alcohol dehydrogenase in humans
Interspecific differences
- Hexobarbital sleeping time after same dose
Sex and age
- Sex-specific differences in certain CYP enzymes
o Why males produce more T and females produce more estradiol - In general, young and very old individuals have LOWER enzyme activities
Diet (nutritional factors)
- Certain ingredients can induce or inhibit phase 1 or phase 2 enzymes
- Ex. grapefruit juice inhibits CYP3A4 in humans)
Disease (underlying pathology)
- Impaired liver or kidney function can decrease biotransformation (and excretion) of drugs
