DRUG CLEARANCE THROUGH METABOLISM

Elimination begins with entry of drug

Major routes of elimination include
Hepatic metabolism
Biliary elimination
Renalelimination
Together, these elimination processes decrease
the plasma concentration exponentially
Constant fraction of the is eliminated in a given
unit of time
• Some drugs are eliminated according to first-
order kinetics
• Aspirin in high doses are eliminated according
to zero-order or nonlinear kinetics
• Metabolism leads to production of products
with increased polarity
• Which allows the drug to be eliminated
• Estimates the amount of drug cleared from the
body per unit of time
Reactions of drug metabolism

• The kidney cannot efficiently eliminate

lipophilic drugs
• Readily cross cell membranes and are
reabsorbed in the distal convoluted tubules
• Lipid-soluble agents are first metabolized
into more polar (hydrophilic)
• Occur in liver via two general sets of
reactions
• Phase I
• Phase II
Phase I reactions
• Convert lipophilic drugs into more
polar molecules
• Introducing or unmasking a polar
functional group such as –OH or
–NH2
• Phase- I reactions usually involve
• Reduction
• Oxidation
• Hydrolysis
• Phase-I metabolism may increase
decrease, or have no effect on
pharmacologic activity
• Phase I catalyzed by the cytochrome P450
system
Phase-II Reaction
• Consists of conjugation reactions
• Subsequent conjugation reaction with an
endogenous substrate
• Glucuronic acid, sulfuric acid, acetic acid
amino acid
• Results in polar, usually more water-soluble
compounds
• Often therapeutically inactive
• Drug possessing an –OH, –NH2, or –COOH
group
• Enter phase II directly and become conjugated
without prior phase I metabolism
Excretion of Drug
Important channel of drug excretion
include
Kidney
Lungs
Bile
Skin
Milk
Saliva
Kidney
• Factor that affect the renal excretion include
• Rate of Glomerular filtration
• Passive tubular reabsorption
• Active tubular secretion
• Rate of Glomerular filtration:
• Limited by the size of capillary pore
• Proceed along the concentration
gradient
• Unionize absorb well but reabsorb
• Ionize drug are excreted entirely and
are not reabsorb from the renal
tubular lumen
• Changing the pH can affect drug
excretion
• Tubular Secretion:
• Most of the acidic and basic drug are
actively secreted by renal tubular cell
• Pump for acidic and basic drug on renal
tubule
• Probenecid compete with penicillin
 Lungs
• Volatile general anesthetic alcohol
aldehyde are partially excreted by lungs
• Paraldehyde and alcohol can be recognized
by the odor
• Bile:
• Ampicillin and erythromycin absorb from
jejunum
• Excreted in bile
• Provide a backup pathway when renal
function is impaired
• Skin:
• Metalloid like arsenic or mercury are
excreted in small amount through skin
• Arsenic get incorporated in hair follicle on
prolong administration
• Use in arsenic poisoning
• Milk and Saliva:
• Unionized drug diffuse easily into milk
• pH of blood and milk differ
• Con of drug will not be same in both
• Penicillin, chloramphenicol, antithyroid
appear in milk and can affect infant
• Potassium iodide and metallic salt are
excreted in saliva