Factors Affecting Drug Metabolism

What are the internal factors and external factors?

Internal Factors

1. Pharmacodynamics

2. Physiological-Nutrition; Disease; Age; Gender & hormones

3. Genetics

External Factors

1. Environmental-exposure to other drugs/xenobiotics

induction/inhibition/DDIs

Alcohol; Diet or Food

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Drugs that undergo 1st pass or pre-systemic metabolism

Pharmacodynamic Factors

Distribution(Serum Protein binding)

Weak acids bind to _______

Weak bases bind to _______

Other serum binding proteins are:

Weak acids bind to albumin

Weak bases bind to alpha-1 acid glycoprotein

Other serum binding proteins are: lipoprotein, alpha, beta, and gamma globulins

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Distribution (serum protein binding)

D + P = DP

Bound drug --> free drug

Bound drug is inactive

Free drug is active

More free drug when binding site are saturated

Competition amound drugs for binding sites leads to DDIs

1. Warfarin

2. NSAIDS(+Cox-2 inhibitors)

3. Sulfonamides

4. Sulfonylureas

5. Depakene

6. Nifedipine

7. Prazosin

8. Diphenhydramine

Coumadin is highly serum protein bound. Sulfonamides bind to the same site as coumadin. If a patient on coumadin also takes sulfonamide what will happen?

A. Toxicity due to high Sulfonamide Levels

B. Coumadin Build up

C. Less coumadin in circulation

D. Extensive Coumadin metabolism

A. Toxicity due to high Sulfonamide Levels

C. Less coumadin in circulation

Uptake

1. OATP - Organic Anion Transport Protein

2. OCTP - Organic Cation Transport Protein

Efflux

1. PGP - P-glycoproteins

2. MDRI gene (Multi Drug resistance P-gps)

3. ABC transporter

Internal Factors

1. Physiological factors

Nutrional status

(Increase/Decrease) lipid & protein intake can (increase/decrease microsomal drug metabolizing activity

How are vitamins and minerals important?

Decreased lipid & protein intake can decrease microsomal drug metabolizing activity

Vitamins and minerals may decrease clearance & increase toxicity

Internal Factors

2. Physiological factors

Disease states

Name the 3 main disease states

1. Liver Disease - depends on importance of metabolism of clearance, toxicity

2. Heart disease  - blood flow

3. Thyroid disease - protein synthesis

Internal factors

3. Physiological factors

Age- fetus

Remember Key Features of Age - fetus

1. CYP450s form very early in gestation; then phase II

2. Common CYP450s - CYP1A & CYP3A7

3. Different balance of metabolism

Phase I >> Phase II (more of Phase I then Phase II)

4. Minimize drug exposure - limit toxicity to the fetus

Internal Factors

4. Physiological factors

Age - Neonates

Remember key features

1. High Phase I and Phase II activity at birth

2. NOT Glucuronidation (inadequate conjugation of bilirubin-a hemoglobin metabolite leads to jaundice or hyperbilirubinemia

3. Avoid drugs that require significant glucuronidation for clearance (ex: chloramphenical or Omeprazole)

Internal factors

5. Physiological factors

Age - Elder

Know the main facts!

1. Less Phase I metabolic activity

due to decreased liver mass and ER

2. Alterations of pharmacokinetics

a. decreased liver blood flow

b. decreased renal filtration rates

c. changed body mass/composition

3. susceptible to toxicity

Internal Factors

6. Physiological factors

Gender & hormones

What are the stress hormones?

______androgens will _____ metabolism

_______ estrogen will ______ metabolism

(increase/decrease)

Gender differences affect what drugs?

Stress hormones: Adrenal, Thyroid

Increased androgens will have increased metabolism

Increased estrogens will have decreased metabolism

Gender differences affect:

1. nicotine

2. aspirin

3. alcohol

4. propanolol

5. diazepam

Internal Factors

7. Physiological factors

Genetics

What are the 4 phenotypic sub populations?

Genetics

1. Dictate DM enzyme differences across/within species

2. Racial or Ethnic population DM enzyme variability

4 Phenotypic sub populations exists

1. Poor metabolizers (PM) - toxicity

2. Intermediate Metabolizers (IM)

3. Extensive Metabolizers - (EM)

4. Ultra-rapid Metabolizers - (UM) - failure

External factors

1. Inducers & inhibitors

Enzyme induction

1. What happens with induction?

2. What are examples of inducers?

3. What is the consequence of the inducers?

1. Induction will

a. increase transcription

b. increased translation

c. decrease protein degradation

2. Examples are : CYPs, UDP-Gt, GST all have inducible forms

Rifampin, phenobarbital, St. John's wort PAH, Phenytoin

3. Induction increases enzyme activity, decreases drug blood levels & duration of action

1. Nevirapine

2. Efavirenz

3. Ritonavir

4. Rifampin

5. Rifabutin

6. Phenobarbital

7. Carbamazepine

8. Phenytoin

9. Alcohol

10. St. John's Wort

External factors

2. Environmental or external factors

Enzyme inhibition

How long does reversible inhibiton last?

How long does irreversible inhibition last?

What happens with enzyme inhibition?

1. Reversible will last 2-3 days

 2. Irreversible last longer because it makes new enzymes

3. Inhibition increases drug activity or toxicity, increased drug blood levels and duration of action: Effect is greater on GI enzymes than on liver because the mass of GI is smaller

1. Protease inhibitors

2. Delavirdine

3. Efavirenz

4. Fluconazole

5. Itraconazole

6. Ketoconazole

7. Voriconazole

8. Iosinazid

9. Ciprofloxacin

10. Grapefruit juice

11. Clarithromycin

12. Erythromycin

13. Diltiazem

14. Verapamil

15. Amiodarone

16. Cimetidine

17. Omeprazole

18. Fluoxetine

External factors

PAH inducers

polycyclic aromatic hydrocarbons

External factors

Dioxane & PCB Inducers

1. 1A2 - ciprofloxacin, cimetidine

2. 2C19 - chloramphenicol, indomethacin

3. 2D6 - cimetidine, chlorpheniramine, cocaine, methadone

4. 3A4, 5,7 - Erythromycin, grapefruit juice, cimetidine, chloramphenicol

External Factors

Furocoumarins in grapefruit juice

1. Allegra               16. Etoposide

2. Theophylline       17. Ifosfamide

3. Cordarone                  18. Tamoxifen

4.Quinidine                    19. Vinblastine

5. Coumadin                   20. Vincristine

6. Tegretrol                    21. Coreg

7. Lipitor                        22. Cardizem

8. Lescol                        23. Plendil

9. Mevacor                     24. Cardene

10. Zocor                       25. Adalat

11. Alfenta                     26. Procardia

12. Duragesic                  27. Nimotop

13. Actiq                         28. Sular

14. Sufenta                     29. Covera

15. Cyclophosphamide      30. Calan

                                     31. Verelan

External Factors

Food or Diet

What foods interact with the CYP1A2?

External factors

Food or diet

What interacts with CYP1A?

External Factors

Food or Diet

What interacts with CYP2E1?

External Factors

Food or diet

What drugs interact with CYP2E1 and CYP1A, CYP3A and Phass II enzymes?

External Factors

Food or Diet

What can influence CYP3A activity?

External Factors

Food or Diet

What can disrupt catechoamine metabolism?

The BIG Picture

Drugs that increase DM activity are _______.

Usually ______ clearance

Drugs that inhibit the DMEs are ___________.

Usually ____________clearance.

Drug that increase DM activity are inducers.

Usually increase clearance.

Drug that inhibit the DMEs are inhibitors.

Usually decrease clearance.