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59-291 Section 1, Lecture 4
Phase I reactions-oxidative occur in the endoplasmic reticulum of
liver (microsomal fractions)
- catalyzed by the microsomal P450 monooxygenase system
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Phase I Biotransformation
• Oxidative reactions
– Catalyzed by enzymes of microsomal fraction
(ER) of liver
• Microsomal cytochrome P450 monooxygenase
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P450 Enzyme Complex
Microsomal cytochrome
P450 monooxygenase
system is a family of
enzymes that biotransforms
many drugs
Fe3+
Fe2+
Hemoprotein
Only Heme-Fe2+ can
bind O=O
Fe3+
Fe2+-O=O
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-many drugs affect the activity of p450 enzymes:
induction or inhibition
-phenobarbital and rifampin
2 drugs that induce
increased transcription and
translation of the P450 genes
Drugs combine with
P450 enzymes and
block their activity
-net result all drugs
metabolized by the P450
system are destroyed and
excreted faster
What are the consequences?
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Hydrolytic reactions:
Cytoplasmic Enzymes Catalyze the hydrolysis (add H2O) or
reduction of drugs
Reductive Drugs
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Phase II Biotransformation
• Conjugation Reactions with endogenous
substances
– Acetylation
• N- acetyltransferase uses acetyl CoA as a source of
acetate
– Glucuronide formation
• Glucuronosyltransferase conjugates glucuronate
molecule with a drug
– Sulfation
• Sulfotransferase sulfonates several drugs. The
sulfate metabolites are active
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Phase II Biotransformation
-here drugs are conjugated (added)
to other molecules
Acetylation- by N-acetyltransferase
enzymes
Glucuronide formation- adds carbohydrate making drugs
more soluble- via glucosyltransferases
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Sulfation- catalyzed by sulfotransferases- sulfated drugs retain
bioactivity
O
R
O
S
OH
O
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Genetic variations in drug biotransformation
-Acetylation slow r/r(Middle Eastern) ; fast r/R or R/R alleles
(Japanese)
-P450- genetic variations in the CYP2D6 4-hydroxylase
-Extensive metabolizers; or
-poor metabolizers no pain relief from codeine prodrug for morphine
catalyzed by CYP2D6 4-hydroxylase
Other genetic variations- 1:3000 occurrence atypical cholinesterasewill not metabolize topical anasthetic succinycholine these individuals
may stay “frozen” for days or weeks- need to be screened for this
enzyme
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Practice questions
(to be discussed in the class)
• 1000 g of a drug is injected to patient and Cp0 was
measured, which is 10 mg/L.
• Where is this drug concentrated mainly? Why?
• Vd=Dose/Cp0 >> Vd= (1g)1000/10= 100
• Since Vd is very large for this drug, more than
total volume of body compartment, it is
concentrated mostly in the cells due to ion
trapping.
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• Identify the phase and type of the following
drug transformation
– Drug-OCH3
Drug-OH + CH2O
• Phase I, O-Dealkylation
– Drug- NH2 + AcetylcoA-CO-CH3
coA-SH + Drug-NH-CO-CH3
Acetyl
• Phase II, Acetylation
– Drug-CH2CH3
Drug-CHOH- CH3
• Phase I, Aliphatic hydroxylation
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