drug metabolism overview dr. arthur roberts 1. where to find information elc – most up to date...
TRANSCRIPT
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Drug Metabolism Overview
Dr. Arthur Roberts
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Where to Find Information
• eLC• www.pharmwiki.org
– most up to date– correct errors
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Outline• Introduction
– ADME– Functions
• Phase I versus Phase II Metabolism– Enzymes– Localization– Regulation
• Phase I Metabolism– Types of Reactions– First Pass Effect
• Phase II Drug Metabolism– Types of Reactions
• Factors that Influence Drug Metabolism• Considerations and Methods
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Metabolites
Drug Metabolism
Excretion
Non-enzymatic
Distribution
Absorption
Blood
Drug
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Functions
• Good – Drug Clearance– Toxin Removal*– Homeostasis and Regulation*– Prodrug (inactive) Active Drug*
• Bad- Reduced Efficacy- Increased Toxicity*
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Functions: Toxin Removalbisphenol A
SulfonationGlucuronidation
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Functions: Homeostasis and Regulation
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Functions: Prodrug Drug
Antidepressant
Antihistamine
(Fura et al., 2004)
Antihistamine
Analgesic
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What is the purpose of a prodrug?
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Functions: Increased Toxicity
Toxic Pathway
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Pathways of Drug Metabolism
Oxidation and Reduction
Conjugation
Drugs
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Phase I versus Phase II?
A
B
C
D
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Why is it called Phase I and Phase II drug metabolism?
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Evans, W. E., and Relling, M. V. (1999) Pharmacogenomics: translating functional genomics into rational therapeutics, Science 286, 487-491.
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Localization: Tissue
Liver Intestines
Kidneys
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Localization: Subcellular
• Phase I– Cytochrome P450s (P450s or CYPs)-ER lumen– Flavin-Containing Monooxygenase (FMO)-ER lumen– Alcohol Dehydrogenase (ADH)-Cytosol
• Phase II– UDP-glucuronosyltransferases (UGTs)- ER lumen– Membrane-bound Sulfotransferases (SULTs)- Golgi
Apparatus– Cytosolic Glutathione-S-Transferases (GSTs)- Cytosol
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What is the purpose of a drug-metabolizing enzyme being membrane bound?
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Regulation
• Induction• Activation• Inhibition
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Regulation: Induction
(Xie, 2004)
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Regulation: Induction
(Xie, 2004)
DNA
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Regulation: Activation
Drug Concentration
Rate
of M
etab
olite
form
ation
Testosterone
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Regulation: InhibitionRa
te o
f Met
abol
ite F
orm
ation
Inhibitor Concentration
Bergamottin
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Phase I “First Pass” Metabolism
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Cytochrome P450Hydroxylations
Dealkylations
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Non-cytochrome P450sAlcohol Dehydrogenase
Epoxide Hydroxylase
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First Pass Effect
• concentration of a drug is greatly reduced before it reaches the systemic circulation.
Morphine Demerol Lidocaine
(opioid analgesic) (synthetic opioid analgesic) (local anesthetic)
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First Pass EffectCo
ncen
trati
on in
Blo
od
Time
Oral
IV
Which corresponds to first pass effect?
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Systems Involved
Liver
Stomach (Gut Wall)
Gastrointestinal
Bacteria
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Phase II Reactions
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Phase II EnzymesGlutathione-S-transferases (GSTs)
N-acetyltransferases (NATs)
UDP Glucuronosyltransferases (UGTs)
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A
B
C
D
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Factors that Influence Drug Metabolism
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Genetics
Poor Metabolizer
Differences in Hydrocodone metabolite formation in Cytochrome P450 2D6
Extensive Metabolizer
(Reynolds, 2008 Clinics in Laboratory Medicine)
34web2.uconn.edu/rusling/Carl_Davis1.ppt
Ethnic Groups
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Aging
(Kinirons, 2003, British Journal of Clinical Pharmacology)
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Gender
[Drug]
Male
Female
Circles=NicardipineTriangles=Nifedipine
Nor
mal
ized
mRN
A Ex
pres
sion
Lev
el
(Konno, 2004 Toxicology and Applied Pharmacology)
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Pregnancy
(Choi, 2011 Biochemical Pharmacology)
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Food, Diet and Nutrition
(Ryu, 2003 Food and Chemical Toxicology)
(Kola nut, grape, green tea and Ginkgo biloba)
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Food, Diet and Nutrition
(Lown, 1997 Journal of Clinical Investigation)
water
chronic grapefruit juice
acute grapefruit juice
Felodipine(Calcium Channel Blocker)
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Obesity
Decreased Metabolism CYP3A4
Increased Metabolism UGTs, NAT, XO, CYP2E1, CYP1A2, CYP2C9, CYP2C19, CYP2D6
(Brill, 2012 Clinical Pharmacokinetics)
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Habits: Alcoholism
A B
A- Non-alcoholicB- Chronic alcohol consumption
(Lieber, 2008 Biochemical and Biophysical Research Communication)
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Habits: Smoking
(Ryu, 2003 Food and Chemical Toxicology)
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Factors that Influence Drug Metabolism
• Genetics• Ethnic Groups• Age• Gender• Pregnancy• Food, Diet and Nutrition• Obesity• Habits (Smoking/Alcohol)
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Ideas on how to deal with these differences?
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End of Overview