Factors Affecting Drug Metabolism

Factors affecting drug metabolism

Drug metabolism is the metabolic breakdown of drugs, through specialised enzymatic systems. Liver is the principal site of drug metabolism, additional sites are kidney, gut, lungs and plasma. Once the drug shows its pharmacological action, the remaining amount of drug should be excreted from body. Metabolism plays an important role in the excretion of drug. The rate of metabolism determines the duration and intensity of drugs pharmacological action. Metabolism also affects multi drug resistance (MDR) in infectious diseases and in chemotherapy. There are various factors affecting drug metabolism including stereochemical aspects as follows,

Table of Contents

Chemical factors
Biological factors
Physicochemical properties of drugs
Stereochemical factors

Chemical factors

Enzyme induction

Enzyme induction is the increased synthesis (higher amount) or decreased degradation (increased activity) of enzymes which occurs due to the presence of drug or xenobiotics. Enzyme induction enhances transcription of CYP450 mRNA which will lead to over production of enzymes in the liver and extra hepatic tissues. This leads to decrease in the concentration of drugs metabolised by the enzyme. Example, aminoglutethimide, barbiturates, carbamazepine, griseofulvin, phenytoin, rifampin, primidone, troglitazone, etc.

Enzyme inhibition

The substances that decrease the metabolising ability of an enzyme are called an enzyme inhibitor. Enzyme inhibitors reduces the compatibility of substrate and enzyme which leads to enzyme-substrate complex formation. Enzyme inhibition is more important clinically than the enzyme induction for drugs with narrow therapeutic index. Examples, allopurinol, aspirin, erythromycin, ketoconazole, methotrexate, etc.

Environmental chemicals

Several environmental agents like halogenated pesticides, cigarette smoke, insecticides, heavy metals, etc. influences the metabolising ability of enzymes.

Biological factors

Age

The rate of drug metabolism in the different age groups differs mainly due to variations in the enzyme content, enzyme activity and hemodynamics.

In neonates (up to 2 months) and in infants (2 months to 1 year), the microsomal enzyme system is not fully developed so many drugs are metabolised slowly. For example, caffeine has a half life of four days in neonates as compared to 4 hours in adults.
Children (between 1-12 years) metabolise several drugs much more rapidly than the adults. The rate of metabolism reaches to maximum between 6 months and 12 years.
In elderly people, functional ability of liver and microsomal activity is decreased. Also, cardiac output decreases leading to less hepatic blood supply. All of these factors decrease the rate of metabolism of drug.

Diet

The enzyme content and activity are altered by number of dietary components. This ultimately affects the rate of drug metabolism.

Enzyme synthesis is promoted by protein diet and also raises the level of amino acids for conjugation with the drugs. Hence low protein diet decreases and high protein diet increases the drug metabolizing ability.
Fat free diet decreases CYP450 enzyme levels, hence rate od drug metabolism also decreases.
Grapefruit juice inhibits metabolism of many drugs and increases their oral bioavailability.
Dietary deficiencies of vitamins (like vitamin A, vitamin B12, vitamin C, vitamin D3, vitamin E) and minerals (like Fe, Ca, Mg, Zn) affect the metabolic activity of enzymes.

Sex

Male and females have different sex hormones, which affects the rate of metabolism. Study shows that women metabolize benzodiazepines slower than men. Women on contraceptive pills metabolize number of drugs at a slower rate.

Pregnancy

During pregnancy women body has elevated concentrations of various hormones such as estrogen, progesterone and prolactin. These hormones affect the hepatic metabolism and responsible for alteration in drug metabolism. For example, during pregnancy women body reduces metabolism of promazine.

Physicochemical properties of drugs

The pharmacological action of drug depends on the interaction between drug molecule and body’s physiological processes. Various physicochemical properties of a drug influence interaction with the active sites of enzyme and site of metabolism. The various physicochemical properties influencing drug metabolism are,

Ionisation
Solubility of drug
Partition coefficient
Hydrogen bonding
Protein binding
Bioisosterism
Optical and geometrical isomerism

Read more about physicochemical properties of drugs.

Stereochemical factors

The interaction of drug molecule with the receptors to generate pharmacological action is affected by stereochemical factors. Isomers of the same drug may react differently with metabolising enzymes. It ultimately affects the rate of metabolism. The pharmacological activity of two enantiomers in racemic mixture may be different.

Summary

Various factors like age, sex, diet, pregnancy, etc can affect how drugs work in our body. Our genes play a big role in enzymatic metabolism, especially in CYP450 enzyme. With the growing age the process of drug excretion changes. Men and women may metabolise drugs differently. Understanding these factors helps medical practitioner to give right dose and avoid the side effects.

Frequently asked questions

How does age affect the drug metabolism?

In general, metabolism tends to slow down in the elderly patients, affecting the excretion of drugs from body. This can lead to need for dose adjustment to ensure safety and efficacy.

What is the role of liver in drug metabolism?

The liver is a primary organ for drug metabolism. Liver plays an important role in enzyme activity, phase I and phase II reactions, biotransformation, clearance of metabolites and inactivation of harmful substances.

What are the factors affecting drug metabolism?

There are various factors which influence the drug metabolism like, chemical factors, biological factors- age, sex, diet, genetic factors and various physicochemical properties of drugs.