Download DRUG ELIMINATION

LECTURE 5
PHARMACOLOGY
DRUG ELIMINATION
Drug Elimination
Sites of Action
Absorption
Unbound Drug
Metabolism
Tissue Depots
Bound Drug
Excretion
Drug Elimination
Direct filtration &
elimination through kidneys
Drug
Metabolism by liver
to inactive product
Active secretion
by kidneys
Metabolism by liver
to active product
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Drug Elimination
Direct filtration &
elimination through kidneys
Drug
Active secretion
by kidneys
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Drug Elimination
• MAJOR ROUTES
– Liver
– Kidneys
• Minor routes of elimination
– Lungs (Volatile general anesthetics)
– Sweat
– Saliva
– Mother’s milk
NEED FOR METABOLISM
KIDNEY Is Major Site of Drug Elimination
Water Soluble
Filtration
Lipid Soluble
in Glomerulus
LIVER
KIDNEY
Lipid soluble drugs
are reabsorbed!!!
Secretion of
organic
acids and
bases
Back diffusion is dependent
on pH of tubular fluid & lipid
solubility of drug
Excretion in Urine
The Kidney
Arterial
supply
Glomerulus
(1.3 L/min)
Collecting
tubule
Proximal
tubule
Distal
tubule
Venous
return
Active secretion
Reabsorption
Urine
e.g., gentamicin, cephalexin
(1.5 L/day)
Loop of Henle
Blood Flow in the Kidney Is Important
• Renal blood flow is ~25% of cardiac output
– 1.3 L/min
• Renal plasma flow is 50% of renal blood flow
– 650 ml/min
• Glomerular filtration rate (GFR) is 20% of plasma flow
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130 ml/min
In 24 hr, 185-190 Liters are filtered by the glomerulus
24 hr urine output is 1.5-1.7 Liters
More than 99% of glomerular filtrate volume must be reabsorbed
• BUT water reabsorption does NOT equal solute reabsorption
Drug Excretion in the Kidney
• Two Components
– Glomerular filtration
• Passive (no energy)
• Clears free drug only
• 130 ml/min
– Tubular secretion
• Active (requires energy)
• Can clear 90-100% of drug flowing through kidney
– 650 ml/min (5X glomerular filtration)
Glomerular Filtration
• The Glomerulus
– Filters 100% of blood supply
– Filters everything <40 kDa
• Plasma & small proteins
• Glomerular Filtration Rate
– ~130 ml/min
– Measured by inulin or creatinine
– Creatinine clearance is a measure of kidney health
• Used to adjust drug dosage if needed
Arterial
supply
(130 ml/min)
Tubular Secretion
• Energy-dependent transport (secretion)
– Occurs from blood into
• Proximal tubule
• Distal tubule
• Loop of Henle
– Can clear blood of 100 of drug passing through kidney
• Separate transport systems for
– Weak organic bases (WOBs)
– Weak organic acids (WOAs)
• Most drugs and metabolites are WOAs
• Probenecid is a substrate for WOA transporters
– Its administration inhibits secretion of many drugs
Tubular Secretion
• Drugs are NOT normal substrates
– Drugs compete with other drugs
– BUT Drugs compete with endogenous metabolites
– In particular metabolic acids
• Sulfate
• Phosphate
• Glucuronate (sugar acids)
– Can cause electrolyte disturbances
Tubular Reabsorption
• Mostly by passive non-ionic diffusion
• Non-ionized forms of drug reabsorbed
– 60% in proximal tubule
– Uric acid (urate) is the exception (active)
THEREFORE
• Acid & base forms of drugs are secreted
• Lipophilic (non-ionic) forms of drugs are reabsorbed
CONSEQUENTLY
• Blood and urine pH affect drug elimination
CLEARANCE
• A very important concept for drug use
• Clearance (Cl) is the VOLUME of fluid (plasma) “cleared”
(freed) of drug per unit time
• Clearance of most drugs is a first order process
– A constant fraction of drug is cleared per unit time
• A fraction is NOT a concentration
• Therefore, first order clearance is independent of drug concentration
CLEARANCE
• Clearance is independent of the method and route of
clearance
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Hepatic clearance
Renal clearance
Lung (inhalational) clearance
Saliva
Mother’s milk
Therapeutic Implications of Clearance
• Highly ionized drugs tend to be rapidly cleared
– Minimal tubular reabsorption since only non-ionized drug is
reabsorbed
• Alkalinizing urinary pH with Na bicarbonate can
accelerate clearance of WOAs
– Salicylate and barbiturates
• Acidifying urinary pH with arginine hydrochloride can
accelerate clearance of WOBs
– Amphetamines
Therapeutic Implications of Clearance
• Drug forms that are quite lipid soluble at the pH of the
urine (5.5) are readily reabsorbed
– Maximal tubular reabsorption since non-ionized drug is
reabsorbed
• Increasing osmolarity of urine (mannitol) may increase
elimination of a lipophilic drug
Therapeutic Implications of Clearance
• Tubular secretion of a drug may be inhibited by another
drug by competition for the transporter
– Probenecid competes with penicillins
• Thus prolongs action of antibiotic
– Probenecid competes with some diuretics (furosemide) and
thus may prevent diuretic access to the tubule which is where
they act
• Decreases effect of diuretic
Therapeutic Implications of Clearance
• Drug clearance is decreased by renal disease
– Measured by creatinine clearance
– Caused by
• Decreased renal blood flow
• Glomerular tubular damage
• Tubular nephropathy
• Drug clearance is greater in an adult than in
– Children (immaturity of kidney function)
– Elderly (decreased renal function
– Alcoholics
Drug Metabolism
•
Most metabolic products are less pharmacologically active
Important exceptions:
• Where the metabolite is more active
(Prodrugs, e.g. Erythromycin-succinate (less irritation of GI) --> Erythromycin)
• Where the metabolite is toxic (acetaminophen)
• Where the metabolite is carcinogenic
•
Close relationship between the biotransformation of drugs and normal biochemical processes occurring in
the body:
– Metabolism of drugs involves many pathways associated with the synthesis of endogenous substrates
such as steroid hormones, cholesterol and bile acids
– Many of the enzymes involved in drug metabolism are principally designed for the metabolism of
endogenous compounds
– These enzymes metabolize drugs only because the drugs resemble the natural compound
Phases of Drug Metabolism
• Phase I Reactions
– Convert parent compound into a more polar (=hydrophilic) metabolite by
adding or unmasking functional groups (-OH, -SH, -NH2, -COOH, etc.)
– Often these metabolites are inactive
– May be sufficiently polar to be excreted readily
• Phase II Reactions
– Conjugation with endogenous substrate to further increase aqueous
solubility
– Conjugation with glucoronide, sulfate, acetate, amino acid
– Phase I usually precede phase II reactions
Liver is principal site of drug metabolism:
– Other sites include the gut, lungs, skin and kidneys
– For orally administered compounds, there is the
“First Pass Effect”
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Intestinal metabolism
Liver metabolism
Enterohepatic recycling
Gut microorganisms - glucuronidases
Drug Metabolism - Phase I
• Phase I Reactions
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Oxidation
Reduction
Hydrolytic cleavage
Alkylation (Methylation)
Dealkylation
Ring cyclization
N-carboxylation
Dimerization
Transamidation
Isomerization
Decarboxylation
Drug Metabolism - Oxidation
Two types of oxidation reactions:
– Oxygen is incorporated into the drug molecule (e.g. hydroxylation)
– Oxidation causes the loss of part of the drug molecule
(e.g. oxidative deimination, dealkylation)
Microsomal Mixed Function Oxidases (MFOs)
•
“Microsomes”
form in vitro after cell homogenization and fractionation of ER
– Rough microsomes are primarily associated with protein synthesis
– Smooth microsomes contain a class of oxidative enzymes called
•
“Mixed Function Oxidases” or “Monooxygenases”
– These enzymes require a reducing agent (NADPH) and molecular oxygen
(one oxygen atom appearing in the product and the other in the
form of water)
Drug Metabolism - Oxidation
• MFO consists of two enzymes:
– Flavoprotein, NADPH-cytochrome c reductase
• One mole of this enzyme contains one mole each of flavin
mononucleotide (FMN) and flavin adenine dinucleotide (FAD)
• Enzyme is also called NADPH-cytochrome P450 reductase
– Cytochrome P450
• named based on its light absorption at 450 nm when complexed with
carbon monoxide
• is a hemoprotein containing an iron atom which can alternate between
the ferrous (Fe++) and ferric (Fe+++) states
• Electron acceptor
• Serves as terminal oxidase
• its relative abundance compared to NADPH-cytochrome P450 reductase
makes it the rate-limiting step in the oxidation reactions
Cytochrome P450
At least 57 different isozymes in humans, over 7700 forms in Nature
isozyme-catalytically and structurally similar but genetically
distinct enzymes-different genes and amino acid sequences
Different isozymes have different substrate specificities
Individuals have several alleles for P450’s and differ in which isozymes they
have
Since individuals have different combinations of P450’s, they differ in their response
to specific drugs
A subset of cytochrome P450’s can be induced, so that more is expressed upon
exposure to a compound.
Because of the number of different isozymes and their different substrates and
inhibitors, the metabolism of a drug can be altered if an individual takes a second
drug.
Some substrates of cytochrome P450 isozymes
1A2
2B6
2C8
2C19
2C9
2D6
2E1
3A4,5,7
amitriptyline
caffeine
clomipr amine
clozapine
cyclobenzaprine
estradiol
fluvoxamine
haloperidol
imipramine NDeMe
mexilletine
naproxen
olanzapine
ondansetron
phenacetin
acetaminophen
propranolol
riluzole
ropivacaine
tacrine
theophylline
tizanidine
verapamil
bupropion
cyclophosphamide
efavirenz
ifosfamide
methadone
paclitaxel
torsemide
amodiaquine
cerivastatin
repaglinide
Proton Pump
Inhibitors:
lansoprazole
omeprazole
pantoprazole
rabeprazole
ibuprofen
meloxicam
S-naproxen
piroxicam
suprofen
Beta Blockers:
Anesthetics:
enflurane
halothane
isoflurane
methoxyflurane
sevoflurane
erythromycin
telithromycin
Anti-epileptics:
diazepam
phenytoin(O)
S-mephenytoin
phenobarbitone
amitriptyline
carisoprodol
citalopram
chloramphenicol
clomipr amine
cyclophosphamide
hexobarbital
imipramine
indomethacin
R-mephobarbital
Oral
Hypoglycemic
Agents:
tolbutamide
glipizide
Angiotensin II
Blockers:
losartan
irbesartan
Sulfonylureas:
glyburide/
glibenclamide
glimepiride
tolbutamide
amitriptyline
clomipr amine
desipramine
imipramine
paroxetine
Benzodiazepines:
cyclosporine
tacrolimus (FK506)
haloperidol
HIV Antivirals
alprenolol
amphetamine
aripiprazole
atomoxetine
bufuralol
chlorpheniramine
chlorpromazine
codeine
Antihistamines:
astemizole
chlorpheniramine
terfenadine
fluvoxamine
lidocaine
metoclopramide
methoxyamphetam
ine
Calcium Channel
Blockers
HMG CoA
Reductase
Inhibitors:
atorvastatin
cerivastatin
Drug Metabolism - Phase II
• Conjugation reactions
– Glucuronidation by UDP-Glucuronosyltransferase:
(on -OH, -COOH, -NH2, -SH groups)
– Sulfation by Sulfotransferase:
(on -NH2, -SO2NH2, -OH groups)
– Acetylation by acetyltransferase:
(on -NH2, -SO2NH2, -OH groups)
– Amino acid conjugation
(on -COOH groups)
– Glutathione conjugation by Glutathione-S-transferase:
(to epoxides or organic halides)
– Fatty acid conjugation
(on -OH groups)
– Condensation reactions
Drug Metabolism - Glucuronidation
• Glucuronidation ( = conjugation to a-d-glucuronic acid)
– Quantitatively the most important phase II pathway for drugs and endogenous
compounds
– Products are often excreted in the bile.
– Enterohepatic recycling may occur due to gut glucuronidases
– Requires enzyme UDP-glucuronosyltransferase (UGT):
• Genetic family of enzymes
– Metabolizes a broad range of structurally diverse endogenous and exogenous compounds
– Structurally related family with approximately 16 isoforms in man
Drug Metabolism - Glucuronidation
•
Glucuronidation – requires creation of high energy intermediate:
UDP-Glucuronic Acid:
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