drug metabolism overview
DESCRIPTION
Drug Metabolism Overview. Dr. Arthur Roberts. Where to Find Information. eLC www.pharmwiki.org most up to date correct errors. Outline. Introduction ADME Functions Phase I versus Phase II Metabolism Enzymes Localization Regulation Phase I Metabolism Types of Reactions - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/1.jpg)
1
Drug Metabolism Overview
Dr. Arthur Roberts
![Page 2: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/2.jpg)
2
Where to Find Information
• eLC• www.pharmwiki.org
– most up to date– correct errors
![Page 3: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/3.jpg)
3
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
![Page 4: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/4.jpg)
4
Metabolites
Drug Metabolism
Excretion
Non-enzymatic
Distribution
Absorption
Blood
Drug
![Page 5: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/5.jpg)
5
Functions
• Good – Drug Clearance– Toxin Removal*– Homeostasis and Regulation*– Prodrug (inactive) Active Drug*
• Bad- Reduced Efficacy- Increased Toxicity*
![Page 6: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/6.jpg)
6
Functions: Toxin Removalbisphenol A
SulfonationGlucuronidation
![Page 7: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/7.jpg)
7
Functions: Homeostasis and Regulation
![Page 8: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/8.jpg)
8
Functions: Prodrug Drug
Antidepressant
Antihistamine
(Fura et al., 2004)
Antihistamine
Analgesic
![Page 9: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/9.jpg)
9
What is the purpose of a prodrug?
![Page 10: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/10.jpg)
10
Functions: Increased Toxicity
Toxic Pathway
![Page 11: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/11.jpg)
11
Pathways of Drug Metabolism
Oxidation and Reduction
Conjugation
Drugs
![Page 12: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/12.jpg)
12
Phase I versus Phase II?
A
B
C
D
![Page 13: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/13.jpg)
13
Why is it called Phase I and Phase II drug metabolism?
![Page 14: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/14.jpg)
14
Evans, W. E., and Relling, M. V. (1999) Pharmacogenomics: translating functional genomics into rational therapeutics, Science 286, 487-491.
![Page 15: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/15.jpg)
15
Localization: Tissue
Liver Intestines
Kidneys
![Page 16: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/16.jpg)
16
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
![Page 17: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/17.jpg)
17
What is the purpose of a drug-metabolizing enzyme being membrane bound?
![Page 18: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/18.jpg)
18
Regulation
• Induction• Activation• Inhibition
![Page 19: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/19.jpg)
19
Regulation: Induction
(Xie, 2004)
![Page 20: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/20.jpg)
20
Regulation: Induction
(Xie, 2004)
DNA
![Page 21: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/21.jpg)
21
Regulation: Activation
Drug Concentration
Rate
of M
etab
olite
form
ation
Testosterone
![Page 22: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/22.jpg)
22
Regulation: InhibitionRa
te o
f Met
abol
ite F
orm
ation
Inhibitor Concentration
Bergamottin
![Page 23: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/23.jpg)
23
Phase I “First Pass” Metabolism
![Page 24: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/24.jpg)
24
Cytochrome P450Hydroxylations
Dealkylations
![Page 25: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/25.jpg)
25
Non-cytochrome P450sAlcohol Dehydrogenase
Epoxide Hydroxylase
![Page 26: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/26.jpg)
26
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)
![Page 27: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/27.jpg)
27
First Pass EffectCo
ncen
trati
on in
Blo
od
Time
Oral
IV
Which corresponds to first pass effect?
![Page 28: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/28.jpg)
28
Systems Involved
Liver
Stomach (Gut Wall)
Gastrointestinal
Bacteria
![Page 29: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/29.jpg)
29
Phase II Reactions
![Page 30: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/30.jpg)
30
Phase II EnzymesGlutathione-S-transferases (GSTs)
N-acetyltransferases (NATs)
UDP Glucuronosyltransferases (UGTs)
![Page 31: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/31.jpg)
31
A
B
C
D
![Page 32: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/32.jpg)
32
Factors that Influence Drug Metabolism
![Page 33: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/33.jpg)
33
Genetics
Poor Metabolizer
Differences in Hydrocodone metabolite formation in Cytochrome P450 2D6
Extensive Metabolizer
(Reynolds, 2008 Clinics in Laboratory Medicine)
![Page 34: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/34.jpg)
34web2.uconn.edu/rusling/Carl_Davis1.ppt
Ethnic Groups
![Page 35: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/35.jpg)
35
Aging
(Kinirons, 2003, British Journal of Clinical Pharmacology)
![Page 36: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/36.jpg)
36
Gender
[Drug]
Male
Female
Circles=NicardipineTriangles=Nifedipine
Nor
mal
ized
mRN
A Ex
pres
sion
Lev
el
(Konno, 2004 Toxicology and Applied Pharmacology)
![Page 37: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/37.jpg)
37
Pregnancy
(Choi, 2011 Biochemical Pharmacology)
![Page 38: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/38.jpg)
38
Food, Diet and Nutrition
(Ryu, 2003 Food and Chemical Toxicology)
(Kola nut, grape, green tea and Ginkgo biloba)
![Page 39: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/39.jpg)
39
Food, Diet and Nutrition
(Lown, 1997 Journal of Clinical Investigation)
water
chronic grapefruit juice
acute grapefruit juice
Felodipine(Calcium Channel Blocker)
![Page 40: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/40.jpg)
40
Obesity
Decreased Metabolism CYP3A4
Increased Metabolism UGTs, NAT, XO, CYP2E1, CYP1A2, CYP2C9, CYP2C19, CYP2D6
(Brill, 2012 Clinical Pharmacokinetics)
![Page 41: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/41.jpg)
41
Habits: Alcoholism
A B
A- Non-alcoholicB- Chronic alcohol consumption
(Lieber, 2008 Biochemical and Biophysical Research Communication)
![Page 42: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/42.jpg)
42
Habits: Smoking
(Ryu, 2003 Food and Chemical Toxicology)
![Page 43: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/43.jpg)
43
Factors that Influence Drug Metabolism
• Genetics• Ethnic Groups• Age• Gender• Pregnancy• Food, Diet and Nutrition• Obesity• Habits (Smoking/Alcohol)
![Page 44: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/44.jpg)
44
Ideas on how to deal with these differences?
![Page 45: Drug Metabolism Overview](https://reader030.vdocuments.mx/reader030/viewer/2022032805/568133e8550346895d9ad926/html5/thumbnails/45.jpg)
45
End of Overview