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CHAPTER 4 (METABOLITES
STORAGE (Storage or reservoir of metabolites in…
CHAPTER 4
METABOLITES
STORAGE
- Storage or reservoir of metabolites in body tissue sometimes occurs. Initially, when a metabolite enters the blood plasma, it may be bound to plasma proteins.
- The primary sites for metabolite storage are adipose tissue, bone, liver and kidneys.
- Lipid-soluble metabolites are often stored in adipose tissue.
- Adipose tissue is located in several areas of the body but mainly in subcutaneous tissue.
- During the normal processes that form bone, Ca2+ and hydroxyl ions are incorporated into the hydroxyapatite- calcium matrix.
- Several chemicals, primarily elements, follow the same kinetics as calcium and hydroxyl ions and therefore can be substituted for them in the bone matrix.
- For example, strontium (Sr) or lead (Pb) may be substituted for calcium (Ca), and fluoride (F-) may be substituted for hydroxyl (OH-) ions. Bone is continually being remodeled under normal conditions. Calcium and other minerals are continually being resorbed and replaced, on the average about every 10 years.
- Thus, any metabolites stored in the matrix will eventually be released to re-enter the circulatory system
- The liver is a storage site for some metabolic products.
- It has a large blood flow and its hepatocytes contain proteins that bind to some chemicals, including metabolic products.
- As with the liver, the kidneys have a high blood flow, which preferentially exposes these organs to metabolic products in high concentrations.
- Storage in the kidneys is associated primarily with the cells of the nephron (the functional unit for urine formation)
- Microsomes rich in enzymes responsible for drugs oxidative metabolism (widest range)
- The enzymes are called MFOs (mixed function oxidases)or monooxygenases which oxidize drugs
- The main TWO microsomal enzymes for drugs metabolism are flavoprotein and hemoprotein.
- Hemoprotein or well known as CYP450 serves as the terminal oxidase
- All isoforms for CYP450 are responsible for oxidizing/reducing the hepatic drugs or xenobiotics in liver
- From research, CYP3A4 alone is responsible for the metabolism of 50% of drugs metabolized in liver
ROLES OF DRUG
METABOLISM
- Detoxify and eliminate plant and bacterial byproducts and toxins
- Detoxify an eliminate drugs and other environmental xenobiotics
- Terminating the biologics activity of some drugs.
- Example: Lipophilic barbiturates (thiopental & pentobarbital). Have a very long life. Metabolic conversion by liver into more water – soluble compounds.
- Metabolic products are often less pharmacodynamically active than the parent drugs or INACTIVE.
- Activate parent drugs or inactive compounds
- Some biotransformation can enhanced activity or toxic properties of xenobiotics.
- This has been exploited by scientist to design inactive prodrugs which only can be converted to active molecules once being metabolized by the liver.
Drugs Metabolism
- Prodrug -> Active metabolite
- Active drug -> Inactive metabolite
- Lipid soluble drug -> Water soluble drug
LIVER:
PRINCIPAL ORGAN
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Some drugs as isoniazid passes through phase II first then phase I (acetylated then hydrolyzed to isonicotinic acid).
Products are generally more water soluble, and are ready for (renal) excretion
PHASE I
Introducing a functional group to parent drug by oxidation, reduction or hydrolysis:
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More chemically reactive; activate the parent drugs or possibly become more toxic, more likely to undergo Phase II metabolism
Possible results from Phase I:
- Drug inactivation
- Conversion of inactive drugs into active metabolite (cortisone -> cortisol)
- Conversion of active drugs into more active metabolite (phenacetin -> paracetamol)
- Conversion to toxic metabolite (methanol -> formaldehyde)
- Oxidation
- Reduction
- Hydrolysis – cleavage of drug molecule by taking up a molecule of water (chemical of a compound breakdown due to reaction with water)
PHASE II
Parent drugs or their Phase I metabolites
often undergo coupling or conjugation
reactions with an endogenous substance
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•Conjugation – Glucuronic acid, amino acid,
(glycine/taurine) glutathione, sulphate,
acetic acid (more and more water solubility)
Conjugation reaction:
- Glucuronidation by UDP-Glucuronosyltransferase:
(on -OH, -COOH, -NH2, -SH groups)
- Sulfation by Sulfotransferase:
(on -NH2, -SO2NH2, -OH groups)
- Acetylation by acetyltransferase:
(on -NH2, -SO2NH2, -OH groups)
- Amino acid conjugation:
(on -COOH groups)
- Glutathione conjugation by Glutathione-S-transferase
- Individual Differences
- Due to genetic factors; enzyme polymorphisms
- Isoniazid is metabolized in the liver via acetylation. There are two forms (slow and fast)
of the enzyme responsible for acetylation (N-acetyl transferase )
- Diet and Environmental Factors
- Conjugating agents are sensitive to body nutrient level. For example, low protein diet can decrease glycine.
- Green tea & grapefruit (CYP3A4)
- Age & Gender
- Reduced in aged patients & children
- Women more sensitive to ethanol (hormones)
- Diazepam, caffeine and paracetamol metabolism is faster in women while propranolol and lidocaine metabolism is faster in men
- Diseases
- Liver Disease – Cirrhosis, Alcoholic liver disease, jaundice, carcinoma
- Cardiac failure causes decreased blood flow to the liver
- Hormonal diseases, infections and inflammation can change drug metabolizing capacity
- Drug Interaction During Metabolism
- They can stimulate (induce) or inhibit microsomal metabolizing enzymes.
- Enzyme induction: phenobarbitone, phenytoin, carbamazepine, rifampicin, griseofulvin, testesterone, some glucocorticoids, tobacco smoking, ethyl alcohol
- Enzyme inhibition: cimetidine, chloramphenicol, erythromycin, oestrogen, progesterone, sodium valproate, cotrimoxazole, isoniazid, ketoconazole and ciprofloxacin
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