Xenobiotic-metabolizing system:

biotransformation of drugs to more polar and therefore excretable products

Most start out lipophilic so they can pass through membranes

-Make a drug more or less active: Pharmacodynamic properties

-Increase clearance and shorten half life: Pharmacokinetic properties

-Increase(tylenol) or decrease toxicity:

Toxicity properties

aka: Functionalization reactions

Expose or introduce a polar group to the parent drug

aka: conjugation reactions

conjugation of an endogenous compound to a phase I product to make a highly polar compound

Liver: 

1st pass effect - oral availability is low because the drug must first pass through the portal system

Sometimes GI, lung, kidney, and skin

In GI, digested by microorganisms, enzymes, and gastric juices

-Most metabolism in the ER and cytosol

-Phase I are usually in ER

-Phase II are usually in cytosol

-Microsomal enzymes: metabolizing enzymes that are located in microvesicles from the ER

Cytochrome P450

NADPH cytochrome P450 reductase

NADPH 

O2

Activated O2 is a very potent oxidating agent

Drugs ONLY need to be lipid soluble to be involved

P450 is very slow by comparison to other catalysts

Arabic # for the family

Capital letter for subfamilies

Arabic # for individual genes

3A4, 2C9, 1A2, 2E1, 2D6, 2C19

3A4 does more than 50% of drugs

Cytosol or ER

Transferases couple activated/energy rich endogenous with exogenous

A phase II reaction:

Most important

Enzyme: UDP-glucuronosyl transferase

Cofactor: UDP-glucuronic acid

Versatile: O-, N-, S- glucuronidations

Phase II

Conjugation with glutathione (GSH)

DETOX

Enzyme: Glutathione transferase

Isoniazid (INH)

Tylenol (some of each, mostly to phase II first)

Age

Sex

Genetic defects

Genetic polymophisms

Dietary factors

Environmental factors

Drug-Drug interactions

Drug-endogenous interactions

N-acetylation of Isoniazid

Slower: polymorphism of NAT2 - parents with 2 NAT2 defects, too much looks like OD

Oxidation/hydroxylation of debrisquin: CYP2D6

3-10% white people = drug pulled

Induce p450 making shorter half lives for drugs :

Charcoal, Cruciferous vegetables, smoking, EtOH (chronic)

Inhibits p450 preventing metabolism:

Grapefruit juice (cyclosporine), acute EtOH

Competitive/reversible: Cimetidine and ketoconazole inhibit p450 by heme iron binding

Irreversible/suicide inhibitors: combine with heme or protein moiety:  

Chloramphenicol, fluroxene; allobarbital; selegiline;  ticlopidine and clopidogrel; phencyclidine; ritonavir and propylthiouracil

Secobarbitol modifies heme and protein moiety

1. Cimetidine, 2. Ketoconozole,

3.  Allopurinol, 4.  Secobarbitol,

5.  Dicumarol, 6.  Disulfiram,

7.  Cyclosporin, 8.  Amiodarone

9.  Fluconazole, 10.  Fluoxetine,

11.  Erythromycin, 12.  Verapamil,

13.  Grapefruit juice, 14.  Alcohol

Generally specific for an enzyme class

ie. CYP3A: Rifampin, Rifabutin, Barbituates, Glucocorticoids, St. John's Wort

Many p450 inducers also induce phase II reactions

Inducers DECREASE pharm action

Autoinducers need increased dosage to prevent tolerance

1. Barbiturates, 2. Phenytoin,

3. Rifampin, 4. Rifabutin, 

5. Carbamazapine, 6. Primidone,

7. Efavirenz, 8. Diet,

9. Smoke, 10. Alcohol,

11. St. John's Wort

Liver: Hepatitis and cirrhosis increase half life of chlordiazepoxide and diazepam

Cancer impaired oxidation of aminopyrine

Heart: Limits blood flow to the liver

Pulmonary: Impairs some metabolism

Heavy metals and porphyria: inhibit liver things

Hypothyroidism can increase half life

Hyperthyroidism can decrease half life

Very young and very old are not good at metabolism

Newborns do phase I and phase II slowly

Age impairs liver

Birth control inhibits some CYPs

2nd and 3rd trimester induce certain metabolic processes.