DRUG METABOLISM

DRUG METABOLISM

DEFINITIONS:

XENOBIOTIC:  This is a compound foreign to the physiology of a living organism.  Drugs are almost all xenobiotics.  Other examples are pesticides and environmentally distributed chemicals in general.

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DETOXIFICATION:  This refers to decrease in biological activity of a drug after it has been metabolized in the body.

TOXIFICATION:  This refers to increase in biological activity of a drug after it has been metabolized in the body.  By this we understand that sometimes metabolism of a drug can result in increase in its activity.  However, in this lecture focus will be on metabolic detoxification of drugs.

BIOTRANSFORMATION:  This is another term for the metabolism of a drug that results in its transformation from a harmful substance to a less harmful product that can easily be excreted from the body.

RENAL EXCRETION AND BIOTRANSFORMATION OF DRUGS.

Biotransformation of drugs leads to termination or alteration of their biologic activity, otherwise most drugs would have a prolonged duration of action.

This is important especially for those drugs that are lipophilic (fat-soluble, or water-insoluble).  They cannot therefore ionize, or rather ionize only partially, at physiologic pH.

For some few drugs however, which are hydrophilic, ionisable compounds, their biologic activity is normally terminated simply by renal excretion (i.e, by being excreted through the urine).

For lipophilic, unionized compounds, because they bind strongly to plasma proteins, they are not easily filtered at the glomerulus of the kidney.  Even though they are filtered, the lipophilic nature of renal tubular membranes makes it easy for them to be reabsorbed into the blood stream.  Consequently, for these compounds (most drugs), termination of biologic activity is not directly by renal excretion, but by metabolic biotransformation.

Lipophilic xenobiotics are usually transformed to more polar and hence readily excretable products, which are less active or even inactive compared to the parent drug.

Note however, that some metabolic biotransformation products have enhanced activity or toxic properties such as mutagenicity (inducing heritable alteration of DNA), teratogenicity (producing birth defects) and carcinogenicity (causing uncontrolled growth of cells and tissues).

LIVER AS THE MAJOR ORGAN OF DRUG METABOLISM.

Although several organs such as gastrointestinal tract, the lungs, the skin, and the kidneys, play important roles in the metabolism of drugs, the liver is the major site of drug detoxification for the following reasons:

1.                 The liver is a large organ.

2.                 It is the first organ perfused by chemical compounds absorbed in the gastrointestinal tract.

3.                 There are very high levels of most drug-metabolizing enzyme systems compared to other organs.

4.                 The liver is well endowed with the smooth endoplasmic reticulum where detoxification occurs specifically.

FIRST-PASS METABOLISM.

Several drugs that are administered orally show limited levels of bioavailability in the parts of the body where its action is required.  This often limits the therapeutic effectiveness of these drugs. 

The reason for this is known as the first-pass effect (first-pass metabolism).  First-pass metabolism is due to extensive metabolism in the liver of many drugs that are absorbed intact (without metabolism) from the small intestine and transported first through the hepatic portal system to the liver.  Examples of such drugs are isoproterenol and morphine. 

Morphine.

Additionally, extensive intestinal metabolism of some orally administered drugs can also contribute to the first-pass effect.  Examples of such drugs are chlorpromazine and clonazepam.

For some drugs, alternative routes of administration other than oral may be employed in order to achieve therapeutically effective levels in the blood.

BIOTRANSFORMATION OF DRUGS

Although metabolic transformation of drugs can occur in the intestinal lumen due to bacterial activity, or in the villi of the intestinal wall, most biotransformations occur between absorption of the drug into blood circulation and its renal excretion.  Nevertheless all biotransformation of drugs in the body occur as either phase I reactions or phase II reactions or both.

PHASE I REACTIONS.

These reactions are also called nonsynthetic reactions.  In phase I reaction a drug is converted to a more polar metabolite by introducing or unmasking a functional group, such as hydroxyl (– OH), amino (- NH2), sulphydryl (- SH), carboxylic acid (- COOH) groups, etc.  These reactions may occur as oxidation, reduction, hydrolysis, cyclization, decyclization, or as carboxylation, etc.

Oxidation enzymes include:

1.                 Cytochrome P450 monooxygenase system.

2.                 Alcohol dehydrogenase.

3.                 Aldehyde dehydrogenase.

4.                 Flavin-containing monooxygenase system.

5.                 Monoamine oxidase.

Reduction enzymes include:

1.                 NADPH-cytochrome P450 reductase.

2.                 Reduced (ferrous) cytochrome P450.

Hydrolysis enzymes include:

1.                 Esterases and amidases.

2.                 Epoxide hydrolase.

STEPS IN MICROSOMAL DRUG OXIDATIONS

Microsomal drug oxidations require cytochrome P450 (so named because it is a hemoprotein which in its reduced (ferrous Fe2⁺) form, binds carbon monoxide to give a ferrocarbonyl compound that absorbs maximally in the visible region of the electromagnetic spectrum at 450nm), cytochrome P450 reductase (an enzyme that contains flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)), NADPH, and molecular oxygen (O₂).  Four steps are involved in the cycle:

1.                 Oxidized, i.e Fe3⁺ cytochrome P450, combines with a drug substrate to form a complex.

2.                 NADPH donates an electron to cytochrome P450 reductase, which in turn reduces the oxidized cytochrome P450 – drug complex.

3.                 Another electron is introduced from NADPH through the same cytochrome P450 reductase, which serves to reduce O₂ to form an “activated oxygen”-cytochrome P450-substrate complex.

4.                 This complex then transfers “activated” oxygen to the drug substrate to form the oxidized product.

Phase I metabolites may be readily excreted at this stage, haven been made sufficiently polar.  Examples of drugs that are metabolized in this way include paracetamol, steroids and phenothiazines.

Paracetamol (para-acetyl-amino-phenol, also called acetaminophen)

PHASE II REACTIONS.

However, many of the phase I products are not eliminated rapidly, and hence undergo a subsequent reaction in which an endogenous substrate such as glucuronic acid, acetic acid or an amino acid combines with the newly introduced functional group to form a highly polar conjugate that is readily excreted in the urine.  Hence phase II reactions are also called conjugation reactions.

Conjugation or coupling reactions require high-energy compounds, and specific transfer enzymes known as the transferases (located in microsomes (endoplasmic reticulum) and the cytosol.  Transferases catalyze either the conjugation of an activated endogenous compound (e.g, uridine 5^’-diphosphate (UDP)derivative of glucuronic acid, i.e, UDP-glucuronic acid) with a drug containing phenol; or the coupling of an activated drug (e.g, S-CoA derivative of benzoic acid, i.e, benzoyl S-CoA,) with an endogenous substrate such as the amino acid glycine.

Phase II conjugation enzymes include:

1.                 Glutathione S-transferases

2.                 UDP-glucuronosyl transferases

3.                 N-acetyltransferases

4.                 Sulfotransferases

5.                 Amino acid N-acyl transferases

FACTORS THAT AFFECT DRUG METABOLISM.

1.                 Induction of drug metabolizing enzymes

2.                 Inhibition of drug metabolizing enzymes

3.                 Physiological factors such as age, individual variation, nutrition and differences in sex

4.                 Pathological factors such as liver, kidney, heart disease, and endocrine dysfunction (such as malfunctions of pituitary, gonads and thyroid).

REFERENCES.

Bhatia S.C (2006), Environmental Chemistry, CBS Publishers and Distributors, India, pg 421 - 423.

INTERNET:  http://en.wikipedia.org/wiki/drug metabolism.

INTERNET:  Common household gadgets, cleaners, and medications are increasing the incidence of autism and cancer,  http://cancerpreventiontheory.info/benzene_in_pain_relievers.htm, 27th January, 2010.

INTERNET:  The role of chemistry in history, http://itech.dickinson.edu/chemistry/?cat=107, 27^th January, 2010.

ASSIGNMENT.

1.                 Define and explain the following terms:  xenobiotics, detoxification, toxification and biotransformation.

2.                 Compare and contrast lipophilic drugs and hydrophilic drugs in relation to their detoxification.

3.                 Discuss renal excretion and metabolic biotransformation of drugs.

4.                 Why do you think the liver is the major organ of detoxification of drugs in the body?

5.                 What do you understand by “First-pass metabolism”?

6.                 What factors do you militate against bioavailability and therapeutic effectiveness of orally administered drugs.

7.                 Discuss phase I reactions of drug biotransformation.

8.                 Discuss phase II reactions of drug biotransformation.

9.                 Outline the steps involved in microsomal oxidation of drugs.

10.            Elaborate on factors that affect drug metabolism.

11.            What contributions do orally administered drugs that are metabolized in the GIT make to the first-pass effect?

12.            What contributions do orally administered drugs that are absorbed intact from the GIT into general circulation make to the first-pass effect.

13.            Discusss Mutagenicity, Teratogenicity and Carcinogenicity in relation to drug metabolism.