Metabolism, Biotransformation, Bioconversion

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1. Biotransformations are summed as _________.

2. Resulting products are called ___________.

3. What is the goal for metabolism?

1. metabolism

2. metabolites

3. Transform lipophilic molecules into hydrophilic ones so that they can be eliminated

Parent molecule -->

Phase 1 metabolite -->

Parent molecule -->

Phase 2 metabolite -->

Parent molecule -->Phase 1 metabolism

Phase 1 metabolite --> Phase 2 metabolism

Parent molecule --> Phase 2 metabolism

Phase 2 metabolite --> Phase 1 metabolism

1. Benoxaprofen

2. Iproniazid

3. Nefazodone

4. Tienillic acid

5. Troglitazone

6. Bromfenac, unclear

1. Decarbazine

2. Dantrolene

3. Felbamate

4. Flutamide

5. Isoniazid

6. Ketoconazole

7. Tolcapone

8. Valproic acid

Reactive metabolites: Acitretin, Bosentan, Gemtuzumab, Ozogamicin, Naltrexone, Nevirapine, Pemoline, Trovafloxacine

1. Acetaminophen

2. Carbamazepine

3. Clozapine

4. Diclofenac

5. Disulfiram

6. Halothane

7. Lefunomide

8. Methyldopa

9. Rifampin

10. Tacrin

11. Tamoxifen

12. Terbinafine

13. Ticlopidine

14. Zileuton

1. Liver (major site)

2. Small Intestine

3. Kidney

4. Skin

5. Lungs (& nasal passage)

6. Plasma

1. Microsomal (Endoplasmic Reticulum)

2. Cytosol

3. Mitochondrial

1. Termination of Drug Action

2. Activation of prodrug

3. Synthesis of similarly active compounds

4. Metabolite with altered activity

5. Bioactivation and toxication

6. Carcinogenesis

7. Tetratogenesis

Activation of Prodrug

Beta-lactam double-ester prodrug

Carcinogenesis

Procarcinogens/toxins activated by CYP450s

Tetratogenesis

R,S Thalidomide

Initially used as a sedative & antimimetic

Now: leprosy and anticancer

Drug Drug Interactions

Some drugs can ______ the synthesis of CYP450 isozymes, hence accelerate the _____________ of drugs utilizing those metabolic pathways and ____________ their plasma levels.

What are the common CYP Inducers?

Ex: Rifampin __ , CYP ___ --> __ HIV protease inhibitors in plasma

Some drugs can induce the synthesis of CYP450 isozymes, hence accelerate the clearance of drugs utilizing those metabolic pathways and decrease their plasma levels.

1. Phenobarbital

2. Rifampin

3. Carbamazepine

Rifampin increase, CYP increase --> Decrease  HIV protease inhibitors in plasma

Drug Drug Interactions

_______ of CYP isozymes, ______ removal of drugs from systemic circulation leading to _______ drug levels because their metabolism is __________.

Common CYP inhibitors: ______, _______,_______

Ex: Omeprazole _____, CYP _____ --> ___ warfarin plasma concentration

Inhibitors  of CYP isozymes, decrease removal of drugs from systemic circulation leading to increase drug levels because their metabolism is inhibited.

1. Erythromycin

2. Ketoconazole

3. Omeprazole

Ex. Omeprazole decreases, CYP decreases --> increases warfarin plasma concentration

1. Ethanol

2. phenobarbital

3.Rifampin

4. Smoking

1. Cimetidine

2. Erythromycin

3. Grapefruit juice

4. Ketoconazole

5. Quinidine

6. Omeprazole