Pharmacokinetics and Drug Metabolism

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Study Notes

Also referred to as "Biotransformation."
It is the chemical alteration of a drug that occurs mostly in the liver.
It aims to convert lipophilic (lipid-soluble) drugs into water-soluble (hydrophilic, ionized, or polar) metabolites.
This conversion facilitates their excretion in urine.
Water-soluble drugs are not metabolized and are excreted unchanged in urine.
Lipophilic drugs can be reabsorbed by the renal tubular cells after filtration through the renal glomeruli, slowing their renal excretion.
Therefore, metabolism converts these drugs into a water-soluble form to facilitate their renal excretion.

They are "Non-Synthetic" reactions.
The drug undergoes oxidation, reduction, or hydrolysis.
Result in one of the following:
- Conversion of an active drug into an inactive metabolite.
- Conversion of an active drug into an active metabolite.
- Conversion of an inactive drug into an active metabolite, also known as a "prodrug".
In rare cases, a toxic metabolite can be formed, such as formaldehyde from the metabolism of methyl alcohol.
Some insecticides, such as Parathion and Malathion, are oxidized into toxic Paraoxon and Malaoxon, respectively.

They are "Synthetic", or "Conjugation" reactions.
The drug, or a metabolite from Phase I, is conjugated with an endogenous polar compound.
These compounds include glucuronic acid, sulphate, glycine, acetate, glutathione, or a methyl group.
Mostly result in drug inactivation, with some exceptions.
Morphine (active) is partially converted into morphine 6-glucuronide (active metabolite).
Minoxidil (inactive) is conjugated into minoxidil sulphate (active).
Most drugs are metabolized by both Phase I and Phase II reactions, or by only one phase.
Some drugs, such as isoniazid, are metabolized by conjugation followed by hydrolysis, reversing the typical order of phases.

The liver is the main site for drug metabolism.
Other locations include the plasma, lung, kidney, skin, and gastrointestinal tract (GIT).

Some drugs increase the activity of HME (HME inducers), while others reduce or inhibit HME activity (HME inhibitors).
HME inducers can lead to tolerance and dependence, increase the metabolism of other drugs, and increase the metabolism of vitamins, leading to potential deficiencies.
HME inhibitors can lead to increased plasma levels of some drugs if administered together, leading to potential toxicity.

Age influences HME activity, which is lower in neonates (especially premature infants) and older adults.

Male sex hormones act as HME inducers, while female sex hormones act as HME inhibitors.
This is an important factor in determining the lower doses for women compared to men.

Liver diseases, such as cirrhosis, can significantly reduce HME activity, requiring dose adjustments based on liver function tests.
Cancer and starvation can also affect HME activity.

There is significant variation in enzyme activity among populations (polymorphism), influencing drug action and toxicity.
Abnormal or defective enzymes can result from genetic defects, causing changes in drug response.
A genetic defect in pseudocholinesterase enzyme significantly reduces the metabolism of succinylcholine (skeletal muscle relaxant).
This can lead to prolonged muscle paralysis, apnea, and even death.
This abnormal drug response due to genetic defect is called "idiosyncrasy."