human physiology

Drug Metabolism
Prof. Patrick Davis
Basic Medicinal Chemical Principles
PHR 143M
Fall-08

Importance of Drug Metabolism
• The basic premise:
Lipophilic Drugs --> Hydrophilic Metabolites
(Not Excreted)
(Excreted)
• Water soluble => increased renal excretion
-anddecreased tubular re-absorption of lipophilics.

Importance of Drug Metabolism
CH 3

CH 2OH

CHO

COOH

OH

O

C 2H 5

Δ1-THC
PC=6000

-

O
C O

O
HO
OH

COO
OH
OH

Excreted
Form
O

C 2H 5

1

Importance of Drug Metabolism
• Metabolism => Termination of Drug Action
– Bioinactivation
-and/or– Detoxification -and/or– Elimination
-and/or-

Importance of Drug Metabolism
• Metabolism => Termination of Drug Action
– Bioinactivation
O
NH2

C O CH2 CH2
Procaine

N

CH2CH3
CH2CH3

O
NH2

C OH

HO CH2 CH2

N

CH2CH3
CH2CH3

Importance of Drug Metabolism
• Metabolism => Termination of Drug Action
– Detoxification
– Disulfiram (Atabuse®)
Atabuse®
N

C

S

S

S

N

C
S

C

N

S

SH HS

C

N

S

2

Importance of Drug Metabolism
• Metabolism => Termination of Drug Action
– Elimination (water soluble).
O
H N C CH3

O
H N C CH3

O
HN C CH3

+
OH
Acetaminophen

O
O S O
OSulfate

O

O

HO
Glucuronide

COO
OH
OH

Importance of Drug Metabolism
• Metabolism => Termination of Drug Action
– Bioinactivation
-and/or– Detoxification -and/or– Elimination
-and/or-

Importance of Drug Metabolism
• Metabolism => Bioactivation
– Active Metabolites
– Prodrugs
– Toxification

3

Importance of Drug Metabolism
• Metabolism => Bioactivation
– Active Metabolites (Surprise! :)

N

N

CH3

(CH2)3 N

H

(CH2)3 N

CH3

CH3
Desipramine

Imipramine

Importance of Drug Metabolism
• Metabolism => Bioactivation
– Prodrugs (by Design!)
CH2COOH

F

CH2COOH

F

CH3

CH3

CH3 S
O

CH3 S
Sulindac
(Prodrug)

Sulindac Sulfide
(Active)

Importance of

References: Chemistry” Edition (2007), Chapter 10 (Drug Metabolism) [your • Goodman & Gilman “Pharmacological Basis of Therapeutics, 11th Edition (2005), Chap 3 (Drug