Drug metabolism and excretion Flashcards
Biotransformation reactions are often subdivided into these two types
Non synthetic
Synthetic
Examples of non synthetic rxns
oxidation
reduction
hydrolysis
phase 1
addition or uncovering of COOH, NH2, O, OH, and/or SH
Examples of synthetic rxns
conjugation
phase 2
addition of group from endogenous cofactor
Where does biotransformation occur
multiple organs; liver is most important
Insertion of oxygen into drug or side product
Phase 1 oxidation rxns
Phase 1 oxidation rxns are catalyzed by
enzyme system with several names:
cytochrome P450 microsomal system (!!!!)
monooxygenase system
mixed function oxidase system
System in phase 1 oxidation rxns that rarely produces reactive metabolites
flavine monooxygenase
Components of P450 system
smooth ER
cytochrome P450
NADPH cytochrome P450 reductase
molecular oxygen
NADPH
Families from cytochrome P450 and function
CYP1
CYP2
CYP3
responsible for most drug oxidation
Important for many clinical drugs
CYP2C
CYP2D
Found in GI tract and is important for first pass effect
CYP3A4 (largest group)
Non-P450 oxidation rxns
Alcohol and aldehyde oxidation (dehydrogenases)
Purine oxidation (xanthine oxidases)
Monoamine oxidation (oxidases: type A and B, inhibitors used as antidepressants)
Other metabolic reactions
Azoreduction
Nitroreduction (chlorampheniol)
Ester hydrolysis (procaine and succinylcholine)
Amide hydrolysis (procainamide and lidocaine)
Type of conjugations phase 2 (conjugation) rxns
glucuronidation (most common)
acetylation
glutathione (important for avoiding drug toxicity)
glycine
sulfation
methylation
Endogenous reactant and enzyme for glucuronidation
uridine diphosphate glucuronic acid; UDP-glucuronyl transferase
Endogenous reactant and enzyme for acetylation
acetyl-coenzyme A; N-acetyltransferase
Endogenous reactant and enzyme for glutathione
glutathione; GSH-S-transferase
Endogenous reactant and enzyme for glycine
glycine; acyl-CoA glycine transferase
Endogenous reactant and enzyme for sulfation
phosphoadenosyl phosphosulfate (PAPS); sulfotransferase
Endogenous reactant and enzyme for methylation
S-adenosylmethionine; methyltransferases
Factors affecting drug metabolism
plasma binding protein
localization/sequestration of drug in tissues
liver disease
drug-drug interactions
Examples of drug-drug interactions
inhibition of drug metabolism
cimetidine
azole antifungals (ketoconazole, macrolide antibiotics, erythromycin)
Induction of drug metabolism
increase in cytochrome P450 proteins
barbiturates (broad)
environmental carcinogens (selective)
chronic alcohol (induces CYP2E1)
Misc. factors affecting drug metabolism
age
diet
disease
other drugs
environmental chemicals
Is formation of toxic metabolites common?
Yes
Toxic metabolites form
electrophilic intermediates that bind to cellular macromolecules
Toxic metabolites cause
necrosis
mutagenesis
carcinogenesis
First defense against toxic metabolites
glutathione conjugation (acetaminophen, acetyl cysteine)
Principal excretion routes
renal
biliary
pulmonary
sweat
saliva
tears
milk
Routes of renal excretion
glomerular filtration
active tubular secretion
passive reabsorption (back diffusion)
active tubular reabsorption
Glomerular filtration occurs at
the glomerular capillaries, high capacity! (180L/day; 20% of plasma)
Requirements for drug filtration
not too large
not bound to plasma proteins
lipid solubility or environmental pH do NOT effect
Active tubular secretion through
organic anion transporters and peptides (OATs and OATPs)
organic cation transporters (OCTs)
Active tubular secretion is not completely developed in
newborns
Is active tubular secretion specific?
no
Is active tubular secretion saturable?
yes
How can the inhibition of drugs such as probenecid effect the renal excretion of weak acids (penicillin)
depress the renal excretion
Active tubular reabsorption is similar to
active tubular secretion
Why is active tubular reabsorption important
to conserve compounds such as uric acid
What inhibits active tubular reabsorption
uricosuric drugs (probenicid and sulfinpyrazone)
Passive reabsorption requires what form of drug
non-ionized
Extent of drug ionization is dependent on
pKa and urinary pH
Urinary pH varies between
5-8; can be manipulated by drugs to increase excretion of acids or bases
When and where does biliary excretion occur
follows phase 2 conjugation in liver
How does biliary excretion occur
through multiple carrier-mediated transport processes
Biliary excretion requires and is
energy; saturable and non-specific
Enterohepatic cycling can occur during
biliary excretion
Liver disease impairs
biliary excretion
Biliary excretion is incompletely developed in
newborns
What drugs can babys not have due to lack of biliary excretion
sulfonamide- induced kernicterus
chloramphenicol- induced gray baby syndrome
can cause hyperbilirubinemia
Pulmonary excretion is important for
gases and volatiles
Pulmonary excretion occurs through
simplified diffusion into expired air
Elimination rate of pulmonary excretion is dependent on
respiration rate
pulmonary blood flow
solubility of drug in the blood: poorly soluble is more rapidly excreted, nitrous oxide > alcohol
Excretion via misc fluids
sweat (dermatitis)
saliva (drug taste)
milk (nursing infants and dairy farming)
Phenobarbital is a
weak acid
Ionized form of phenobarbital is
excreted
Alkaline urine increases fraction in what form
how does this effect excretion and reabsorption
ionized; increases excretion and reduces reabsorption
How to increase excretion of amphetamine
acidify urine
How to increase excretion of phenobarbital
alkalinize urine
Amphetamine is a
weak base
What form of amphetamine is excreted
ionized
Acidic urine increases fraction in what form
how does this effect excretion and reabsorption
ionized; increases excretion and reduces reabsorption
