Lesson 9 Drug Elimination Process

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Lesson 9Drug Elimination Process
About Metabolism Excretion

• ??????? 9?
• ??? ???
• ??? ???

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1. Drug Elimination

• Elimination(??)
• Metabolism(??) Excretion(??)
• ??? Elimination? ???? ??
• ? ?, ??
• ? ? ??? ??? ??
• ? ?? ??? ??? ??

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1. Drug Elimination

• Lipophilic drug
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• ? ???? ??? ????
• ? ???? ?? ??? ???
• Hydorphilic drug (ionized)
• ? ??? ??
• ? ???? ??? ??

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1. Drug Elimination

• Metabolism (biotransformation)
• ??? ??? ?? ??? ???? ?
• Active metabolite / Inactive metabolite
• - procainamide, encainide
• ? ???? ?? ??? ??
• Prodrug
• ??? ???? ?? ?? ??? ??? ??
• - ACE inhibitor

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1. Drug Elimination

• Km ?? ??? ?? ???? ???? ??
• Kr ??? ??? ?? ???? ???? ??

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1. Drug Elimination

• Kr gtgt Km
  Km gtgt Kr

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1. Drug Elimination

• ?? ??
• - hepatic lobule(???) ??? ?? ??
• - hepatic artery(???) 350ml/min
• - portal vein(???) 1100ml/min
• - sinusoid
• - central vein
• Portal triad
• Sinusoid
• - ??? ???? ??

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1. Drug Elimination

• Hepatic drug metabolism
• (1) phase 1 reaction (preparatory reaction)
• - ??, ??, ????
• - Cytochrome P450 enzyme
• (2) phase 2 reaction (conjugation reaction)
• - ? ??? ?? ?? ?? ??
• Cytochrome P450
• - Common gene 4054 / 5596 / 97??
• (e.g CYP3A3, CYP3A4)
• ? induction, inhibition

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2. Biotransformation

• ????? ??? ?? ??
• - ?? ??, ??
• - ??? ?? ??, ??
• - ?? ? ??, ??
• - ?? ??
• - ??? ??

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3. Hepatic clearance

• Hepatic excretion
• - high 80 ??
• - intermediate
• - low 20 ??
• Extraction ratio (E)
• - high extraction ratio 1? ???
• - low extraction ratio 0? ???

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3. Hepatic clearance
?? ?? ?? ????? ?? ?? ?? Hepatic
clearance - Clh hepatic drug clearance -
Fp fraction of free drug in plasma - Cli
intrinsic clearance - Qh hepatic blood flow
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3. Hepatic clearance

• Intrinsic clearance (?????)
• - ???? ???? ????? ?? ?? ???
• ??? ????? ?? ???? ?? ?????
• QhltltCli (???? ? ??)
• - ???? ????
• QhgtgtCli (???? ?? ??)
• - intrinsic clearance? ????

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4. First-Pass effect

• ? ?? ?? (first-pass effect)
• - ????? ??? ??? ?????? ????
• ??? ??? ???? ?
• - ?? ???? ? ?????? ???? ???
• - propranolol
• Oral dose(F)

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5. Effects of disease states and drug
interaction

• Example 1 ?????? ??? ??
• Theophyline
• ? IV infusion
• ? ?? ???
• ? ?? ???? ??
• ? Cimetidine (cytochrome P450 ???) ??
• CSS(total) 2?? ??
• CSS(free) 2?? ??
• ?Theophyline ??? ½? ??

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5. Effects of disease states and drug
interaction

• Example 2 ????? ?? ??????
• Phenytoin
• ? intermittent IV
• ? ?? ???
• ? ?? ???? ??
• - ???? 90?80
• CSS(total) ½? ??
• CSS(free) ?? ??
• ? ???? ?? ??

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5. Effects of disease states and drug
interaction

• Example 3 ?????? ?? ???? ??
• Lidocaine
• ? IV infusion
• ? ?? ???
• ? acid glycoprotein? ?? ?? ???? ??
• CSS(total) ?? ??
• CSS(free) ??
• ? Lidocaine ??? ??

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6. Renal elimination

• Elimination(??)
• Metabolism(??) Excretion(??)
• Total body elimination
• ???? ?? ???? ?? ??? ??
• Excretion(??)
• ??? ?????? ??? ???? ??

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6. Renal elimination

• Renal Excretion? ??
• ? ??? ??
• ? ?????? ??
• ? ?????? ???
• (1) ??? ??? ??
• ? ???
• ? ????
• ? ???? ?, ???? ??
• (2) ??? ??? ?? ??? ??
• (3) ??? pH? ??

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6. Renal elimination

• Renal clearance? ??

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6. Relationship between renal clearance and
glomerular filtration rate

• Clearance (slope)(GFR) 0
• Clearance (slope)(GFR) y-intercept
• Y mx b

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6. Relationship between renal clearance and
glomerular filtration rate

• Creatinine clearance? aminoglycoside
• K 0.00293hr-1 X creatinine clearance 0.014

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6. Relationship between renal clearance and
glomerular filtration rate

• Patient specific creatinine clearance
• U urinary creatinine
  concentration
• V volume of urine collected
• P plasma creatinine
  concentration
• 1440 24??? ??? ??
• Cockcoft-Gault equation
• Ideal body weight
• Adjusted body weight

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1. Drug Elimination
??? ????

• ?