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 OH
-

CH 2OH

CHO

COOH

O 1-THC PC=6000

C 2H 5

O C O

O HO OH

COO OH OH

Excreted Form O C 2H 5

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 O NH2 C OH HO CH2 CH2 N N CH2CH3 CH2CH3

CH2CH3 CH2CH3

Importance of Drug Metabolism

Metabolism => Termination of Drug Action
Detoxification Disulfiram (Atabuse) Atabuse
N C S S S C S N

C S

SH HS

C S

Importance of Drug Metabolism

Metabolism => Termination of Drug Action
Elimination (water soluble).
O H N C CH3 O H N C CH3 + OH Acetaminophen O O S O OSulfate O HO Glucuronide COO OH OH O HN C CH3

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

Importance of Drug Metabolism

Metabolism => Bioactivation
Active Metabolites (Surprise! :)

N (CH2)3 N

CH3 CH3

N (CH2)3 N

H CH3

Imipramine

Desipramine

Importance of Drug Metabolism

Metabolism => Bioactivation
Prodrugs (by Design!)
F CH2COOH CH3 F CH2COOH CH3

CH3 S O Sulindac (Prodrug)

CH3 S Sulindac Sulfide (Active)

Importance of Drug Metabolism

Metabolism => Bioactivation
Toxification (toxigenic metabolism; Oops!)

N CH3 MPTP

+N CH3 MPDP

+N CH3 MPP+ (Neurotoxin)

Importance of Drug Metabolism

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

Metabolism => Bioactivation

Active Metabolites Prodrugs Toxification

Importance of Drug Metabolism

Metabolism => Drug Interactions
O OH P-450

Metabolite(s) (Inactive) Chloramphenicol (Antibiotic)

O O Warfarin (Anticoagulant)

Is This Just Hype?

N H3C N S N N N N N NO2 SH N Xanthine Oxidase HO SH N N N OH N H Azathioprine (Imuran) N H 6-Mercaptopurine (Active) N H 6-Thiouric Acid (Excreted)

How Real Is This?

N H3C N S N N N NO2 SH N Allopurinol Xanthine Oxidase

N N H Azathioprine (Imuran)

N N H 6-Mercaptopurine (Toxic)

Allopurinol Colchicine Corticotropin Ibuprofen Prednisolone Prednisone Probenecid Sodium Thiosalicylate Sulfinpyrazone Triamcinolone

Importance of Drug Metabolism

Stereochemical Implications of Metabolism
CH3 COOH H CH3 H COOH R-Ibuprofen (Inactive) S-Ibuprofen (Active)

Importance of Drug Metabolism

Stereochemical Implications of Metabolism
CH 3 N R O CH 3 N R O COOH H COOH H S-Benoxaprofen (Active) Elderly Oraflex R-Benoxaprofen (Inactive) Toxicity

R = p-chlorophenyl

Importance of Drug Metabolism

Control of Metabolism Through Drug Design If you can predict metabolic pathways =>
Avoid toxigenic pathways.
cytotoxicity, carcinogenicity, mutagenicity risk assessment (drug development) acute vs long-term therapy

Speed up metabolism?? Why?? Slow down metabolism?? Why??

Importance of Drug Metabolism Review

Termination of Drug Action Bioactivation Drug Interactions Stereochemical Implications Control of Metabolism Absolutely Required by FDA
Clearly affects efficacy efficacy Clearly affects toxicity toxicity

Importance of Drug Metabolism Understanding It

Practice problems: Foyes Med. Chem. Liver Game (class exercise). Online Practice Quizzes.* [Do Pre-Test Now] Previous Exams (view as practice problems).* Flash Metabolism Tutorials* Blackboard Discussion Board; Office Hours; eOffice Hours* Concept Map Lab
*[http://courses.utexas.edu or UTDirect]

Drug Metabolism References

Foyes Principles of Medicinal Chemistry, 6th Foye Chemistry Edition (2007), Chapter 10 (Drug Metabolism) [your required text]. Goodman & Gilman Pharmacological Basis of Therapeutics, 11th Edition (2005), Chap 3 (Drug Metabolism) [your required text]. Online references [Blackboard website] PRACTICE DRAWING PATHWAYS!

Phase-1 vs. Phase-2 Metabolism

Prof. Patrick Davis Basic Medicinal Chelmistry Principles PHR 143M Fall-08

Phase-1 Metabolism Description

Phase 1 = "Functionalization" Reactions
New polar functional groups. Interchange existing functional groups Unmask existing polar groups.

Phase-1 Metabolism Description

Reactions include:
Oxidations (hydroxylations) = new RH --> ROH Reductions = interconversion C=O --> CH-OH Hydrolyses = unmasking R-CO2CH3 --> RCOOH + CH3OH

Phase-1 Metabolism Description

Purpose:
enhance excretion RH --> ROH (more water soluble) prepare for phase 2 RH --> ROH (functional handle)

Phase-2 Metabolism Description

Phase 2 = "Conjugation" Reactions
Acts on parent drug or Acts on phase 1 metabolite.

Links to endogenous, polar, ionizable cpd. Purpose: enhance excretion. Reaction types include:
O H N C CH3 O H N C CH3

O HN C CH3

Glucuronidation Sulfate formation

+ OH Acetaminophen O O S O OSulfate O HO Glucuronide COO OH OH

Phase-1 & Phase-2 Complimentary NOT Mutually Exclusive

R Phase 1 NH2 R HO NH2 Phase 2 R O -O S O O

NH2

Excretion

Principle Sites of Drug Metabolism

Liver
Major xenobiotic metabolism nonessential exogenous (foreign) compounds Major endobiotic metabolism endogenous compounds The Presystemic "First pass effect"

Principle Sites of Drug Metabolism

General Systemic Circulation Portal Vein

Liver

Stomach

Intestine

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Presystemic First Pass Effect

Source:
Hepatic first pass metabolism. Metabolism by GI mucosa during absorption.

Significance?
regular drugs prodrugs See Foyes Table 8.13

How Overcome?

Principle Sites of Drug Metabolism

GI Tract
Epithelium very rich in drug-metabolizing enzymes; phase-1 and phase-2 (significant contribution oral bioavail) Gut flora
Reduction (e.g. azulfidine) deconjugation (e.g. premarin) enterohepatic recycling (EHC)
Endobiotic = bile salt recycling Xenobiotic = conjugates >500 MW excreted by pglycoprotein and MDR-2 transport systems into bile.

Principle Sites of Drug Metabolism

Liver GI Tract Kidneys, Lungs, Brain, etc
localized bioactivation (e.g. PAHs in cigarette smoke) localized toxicity (e.g. MPTP)

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Phase-1 vs. Phase-2 Metabolism

Prof. Patrick Davis Basic Medicinal Chemical Principles PHR 143M Fall-07

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