DRUG METABOLISM

XOH
Phase I Phase II
O2 ROH
X X XOH XOR XOR
CYP450 UGT MRP
P-gp

Cell (hepatocyte) Elimination

Phase I: functionalization (increase polarity)

Phase II: conjugation (increase watersolubility)

: expulsion of unchanged or conjugated xenobiotics

BASIC REACTION CATALYZED BY CYP450

Substrate (RH) + O2 + NADPH + H+

product (ROH) + H2O + NADP +

 CYP450, XENOBIOTICS AND ENDOBIOTICS

Detoxication or activation to toxic Biosynthesis and

and/or tumorigenic metabolites catabolism
XENOBIOTICS ENDOBIOTICS
Cholesterol
Drug metabolism Steroid hormones
Toxicants Bile Acids
Pesticides Fat soluble vitamins (A and D)
Pollutants Fatty Acids
Carcinogens Retinoic Acid
Food additives Eicosanoids
NOMENCLATURE OF CYTOCHROMES P450

CYP 2 D 6 *4

genetic superfamily
family
sub-family
isoenzyme
allelic variant
SOURCE
http://www.cypalleles.ki.se/
 QUANTITATIVE DISTRIBUTION OF THE
ISOFORMS IN THE LIVER
other CYP1A2
5% 10 % CYP2B6
5%
55%
CYP3A 10%
CYP2C9 20 %
40 % *
CYP2C19

CYP2E1
CYP2D6
* 5%

Contribution *5 %
10 %
to drug 30% *polymorphic CYP
metabolism
 MODULATORS OF CYP ACTIVITY

CYP inducers
Increase
activity Ultrarapid
metabolizers

CYP inhibitors
Decrease Poor metabolizers
activity
Diseases
Ultrarapid (UM)
4 GROUPS OF
Normal (NM) METABOLIZERS
OF CYP2D6
Intermediate (IM)

Poor (PM)
 PHENOTYPE-GENOTYPE RELATIONSHIPS

or or or or
Genotype

Surexpressed Normal Unstable Absent

enzyme enzyme enzyme enzyme

Ultrarapid Normal Intermediate Poor

Phenotype metabolizer metabolizer
metabolizer metabolizer
UM NM IM PM
Frequency 5-10% 65-80% 10-15% 5-10%
in Europe
 POLYMORPHISM OF CYP2D6

6% 10% 1%

3%
4% 5%
POOR METABOLIZERS OF
CYP2D6
 POLYMORPHISM OF CYP2D6

1%
8%
5%
0.5%

5% 10% 3%
30%
2%
ULTRARAPID 20%
METABOLIZERS OF 3%
CYP2D6