1

Drug Metabolism Overview

Dr. Arthur Roberts

2

Where to Find Information

• eLC• www.pharmwiki.org

– most up to date– correct errors

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

4

Metabolites

Drug Metabolism

Excretion

Non-enzymatic

Distribution

Absorption

Blood

Drug

5

Functions

• Good – Drug Clearance– Toxin Removal*– Homeostasis and Regulation*– Prodrug (inactive) Active Drug*

• Bad- Reduced Efficacy- Increased Toxicity*

6

Functions: Toxin Removalbisphenol A

SulfonationGlucuronidation

7

Functions: Homeostasis and Regulation

8

Functions: Prodrug Drug

Antidepressant

Antihistamine

(Fura et al., 2004)

Antihistamine

Analgesic

9

What is the purpose of a prodrug?

10

Functions: Increased Toxicity

Toxic Pathway

11

Pathways of Drug Metabolism

Oxidation and Reduction

Conjugation

Drugs

12

Phase I versus Phase II?

A

B

C

D

13

Why is it called Phase I and Phase II drug metabolism?

14

Evans, W. E., and Relling, M. V. (1999) Pharmacogenomics: translating functional genomics into rational therapeutics, Science 286, 487-491.

15

Localization: Tissue

Liver Intestines

Kidneys

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

17

What is the purpose of a drug-metabolizing enzyme being membrane bound?

18

Regulation

• Induction• Activation• Inhibition

19

Regulation: Induction

(Xie, 2004)

20

Regulation: Induction

(Xie, 2004)

DNA

21

Regulation: Activation

Drug Concentration

Rate

of M

etab

olite

form

ation

Testosterone

22

Regulation: InhibitionRa

te o

f Met

abol

ite F

orm

ation

Inhibitor Concentration

Bergamottin

23

Phase I “First Pass” Metabolism

24

Cytochrome P450Hydroxylations

Dealkylations

25

Non-cytochrome P450sAlcohol Dehydrogenase

Epoxide Hydroxylase

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)

27

First Pass EffectCo

ncen

trati

on in

Blo

od

Time

Oral

IV

Which corresponds to first pass effect?

28

Systems Involved

Liver

Stomach (Gut Wall)

Gastrointestinal

Bacteria

29

Phase II Reactions

30

Phase II EnzymesGlutathione-S-transferases (GSTs)

N-acetyltransferases (NATs)

UDP Glucuronosyltransferases (UGTs)

31

A

B

C

D

32

Factors that Influence Drug Metabolism

33

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

35

Aging

(Kinirons, 2003, British Journal of Clinical Pharmacology)

36

Gender

[Drug]

Male

Female

Circles=NicardipineTriangles=Nifedipine

Nor

mal

ized

mRN

A Ex

pres

sion

Lev

el

(Konno, 2004 Toxicology and Applied Pharmacology)

37

Pregnancy

(Choi, 2011 Biochemical Pharmacology)

38

Food, Diet and Nutrition

(Ryu, 2003 Food and Chemical Toxicology)

(Kola nut, grape, green tea and Ginkgo biloba)

39

Food, Diet and Nutrition

(Lown, 1997 Journal of Clinical Investigation)

water

chronic grapefruit juice

acute grapefruit juice

Felodipine(Calcium Channel Blocker)

40

Obesity

Decreased Metabolism CYP3A4

Increased Metabolism UGTs, NAT, XO, CYP2E1, CYP1A2, CYP2C9, CYP2C19, CYP2D6

(Brill, 2012 Clinical Pharmacokinetics)

41

Habits: Alcoholism

A B

A- Non-alcoholicB- Chronic alcohol consumption

(Lieber, 2008 Biochemical and Biophysical Research Communication)

42

Habits: Smoking

(Ryu, 2003 Food and Chemical Toxicology)

43

Factors that Influence Drug Metabolism

• Genetics• Ethnic Groups• Age• Gender• Pregnancy• Food, Diet and Nutrition• Obesity• Habits (Smoking/Alcohol)

44

Ideas on how to deal with these differences?

45

End of Overview