Metabolism of Drugs | Pharmacokinetics

After reading this article you will learn about: 1. Definition and Need of Metabolism 2. Types of Metabolism.

Definition and Need of Metabolism:

Metabolism is a process of alteration of drugs in the body so as to modify their activity and structure.

If lipophylic drugs are not metabolized it will be reabsorbed by the kidney tubule and will circulate in the blood for months together. The long persistence of a drug in the animal’s body can create many toxicological and health hazard problems. After metabolism, a drug is converted into polar (water soluble) or less lipid soluble compound and hence, they are readily excreted from the body.

1. Pro Drugs:

Pro drugs are inactive drugs and are converted into their active forms after metabolism.

As for example:

Prontosil – Sulphanilamide

Castor oil – Recinoleic acid

Sodium citrate – Sodium bicarbonate

Codein – Morphine

2. Primary Organs of Metabolism:

Liver is the primary organ of metabolism. However, drugs are also metabolized into cytoplasm, mitochondria, blood-plasma etc. The drugs are also metabolized by micro-organisms present in gastrointestinal tract especially in rumen.

The drug metabolizing enzyme system is located in the smooth endoplasmic reticulum are known as microsomal enzymes e.g. mixed function oxidases, reductases, esterases, uridine diphosphate, glucuronic acid transferase (UDPGA transferase) etc.

There are certain drugs that can increase or decrease the activity of drug metabolizing enzymes. The drugs which decrease the rate of drug metabolism by inhibiting the enzymes involved are known as enzymes inhibitors e.g. Chloramphenicol, carbon tetrachloride, guanidine, organophosphorus insecticides, ether, ethanol, estrogen, progesterone, hepatotoxic drugs, tolbutanide etc.

3. Enzyme Induction:

Enzyme Induction drugs that increase the rate of metabolism by inhancing the activity of metabolizing enzymes e.g. Chloroform, chlorpromazine, pethidine, phenylabutazone etc. If both, enzymes inhibitors and inducers are prescribed at a time the situation may be a different than the normal one.

The drugs are metabolized in two phases. In first phase they are put to various reactions like oxidation, reduction and hydrolysis. In the second phase when some of the functional groups like -OH, -COOH, and -NH₂ are unmasked or have been introduced they are conjugated.

Types of Metabolism:

The types of metabolism may be classified in two groups:

A. Non-synthetic metabolism:

1. Oxidative Metabolism:

It is mediated by the liver microsomal enzyme system. Microsomal oxydation is the most prominent reaction in the metabolism of lipid soluble drugs and steroid hormones.

These enzymes are located in the smooth surfaced endoplasmic reticulum. These enzymes have a specific requirement for reduced nicotinamide adenine dinucloeotide phosphate (NADPH) and molecular oxygen and are known as mixed-function oxidases.

There are various kind of oxidative reactions as listed below:

(i) Aromatic hydroxylation

(ii) Aliphatic oxidation

(iii) O-de-alkylation

(iv) N-de-alkylation

(v) Oxidative deamination

(vi) Desulfuration

(vii) Sulfoxidation

i. Aromatic Hydroxylation:

e.g., conversion of acetanilid to p- hydroxy acetanilid.

ii. Aliphatic Oxidation:

Aliphatic Oxidation is also known as side chain oxidation e.g.,

Aromatic esters are cleaved by this reaction.

iii. N-Dealkylatoin: e.g.,

iv. Oxidative Deamination:

e.g., the metabolism of amphetamine to phenyl acetone by rabbit liver is an example of this type of oxidation;

v. Desulfuration:

Desulfuration means replacement of sulfur by oxygen.

vi. Sulfoxidation: e.g.,

2. Reduction:

e.g., Azo and nitro reduction.

3. Hydrolysis:

This is restricted to esters and amides. Esterases and amidases are hydrolytic enzymes found in blood plasma and other tissues, including the liver, usually in the soluble fraction of the cells.

The hydrolytic reactions are shown below;

B. Synthetic Metabolism:

Drug molecules having functional groups like -OH/ -COOH, -NH₂ undergo conjugation with endogenous substances like glucuronic acid, acetate, (acetylation), sulfate (sulfuric acid ester formation) and various amino acids. The conjugated drugs are water soluble and pharmacologically inactive.

The conjugating agents do not react directly with the drug or its phase I metabolite. They react either in an activated form or with an activated form of the drug. These activated forms are usually nucleotides. The reaction between nucleotide and drug or conjugating agent is catalysed by an enzyme.

A conjugation reaction needs a conjugating agent, a nucleotide containing either the conjugating agent or the foreign compound and a transferring enzyme. In certain animals synthetic reactions are either defective or absent.

As for example cat synthesizes glucuronic conjugates at a slow rate, because cat is deficient in transferring enzyme, glucuronyl transferase. Acetylation is absent in dog, fox and turtles. Glucuronidation is absent in fish. In insects glucuronide formation is replaced by β-glucoside conjugation.

Example of Drugs that are Excreted as Glucuronide:

morphine, salicylates, acetaminophen, chloramphenicol, sulfadimethoxine, oxazepam, oxyphenbutazone, pentobarbital, phenytoin etc.

What is Important:

Glucuronides are more water soluble than the parent drugs and are ionize at physiological pH. They are easily removed from the body because of their decreased extravascular distribution and they are more soluble substrates for carrier-mediated excretion into urine and bile.

It is the molecular weight of a compound that determines whether the drug will be excreted in bile or not. The route of excretion may predominate for compounds with molecular weight above 500 and is relatively common in rats, dogs, and chickens than in other species.

Glucuronides that are excreted in bile may be hydrolysed by β-glucuronidase in the intestine. The hydrolysis of glycuronides can liberate the drug which can be reabsorbed and an enterohepatic cycle may be established.

Example of synthesis of glucuronide is given below:

Acetylation:

Co-enzyme A (Co A), reacts with an activated form of a carboxilic acid to form acetyl-Co A derivative. The acyl group is then transferred to a suitable accepter such as an aromatic amine. Acetylating enzymes are located in the soluble fraction of liver. Gastrointestinal mucosal cells can also acylate several drugs.

Example of acylation is given as below:

Metabolism of Drugs in Gastrointestinal Tract:

Gastrointestinal microflora also meditate metabolic transformation of many drugs through hydrolytic and reductive reactions. Evidence has been recorded for activation of anthraquinone glycosides through bacterial enzymes in large intestine of animals.

The enzyme responsible for hydrolysis of glycuronide conjugates i.e. β-glucuronidase is found in Escherichia coli of large intestine. Cardiac glycosides are hydrolysed and inactivation of chloramphenicol by ruminal microflora has also been evidenced.

If it is essential to administer antibiotics for a long duration, clinicians must think that these agents adversely affect the activity of microflora located in rumen and large intestine. It hardly matters whether these agents are given orally or parentally.