Pharmacokinetics Metabolism and Excretion

Drug elimination is an?

• Irreversible Process

What are the 2 Steps to Drug Elimination?

• metabolism (biotransformation) 

• And/or excretion

 The effect that a drug has on the body is therefore not only dependent on its pharmacological actions but also?

• On how the Body handles it.

the main sites of metabolism and excretion are?

• Metabolism = Liver

• Kidneys = Excretion

The products of metabolism are generally more?

• Water soluble than the Original Compound

Drug metabolism involves two types of reactions known as?

• Phase 1 & Phase 2

Phase 1 reactions involve the?

• Involve the enzymatic introduction of a functional group which generally make the molecule less lipophilic,

• and so reduces the possibility of its reabsorption in the renal tubules

Phase 2 reactions involve?

• Conjugation Reactions

• that generally result in inactive products which are more hydrophilic (water soluble) 

The metabolites from phase 1 reactions may be pharmacologically less active but the?

• The Products (Metabolites) may be more Active/ Reactive

Some drugs, known as prodrugs, are administered?

• administered in a pharmacologically inactive form

• to facilitate absorption, and require metabolism in the body to become active.

• E.G Codeine

Phase 1 reactions frequently result in the formation of?

• Stable Metabolites

• which may be less lipophilic

• and have a lower or no pharmacological activity

Drugs can be metabolised into a products called?

• Metabolites

Metabolites have pharma…

• Pharmacological  Activity

• Metabolites can prolong the duration of effect. E.G Diazepam

Some drugs, prodrugs, are administered in an inactive form that?

• Requires metabolism that to form the pharmacological active metabolite E.G Codeine

For some drugs one of their metabolites can be?

• Chemically reactive

These reactive metabolites can cause?

• Cellular Damage & Toxicity

• When produced in high enough quantities e.g. paracetamol

Most drugs will undergo several metabolic reactions concurrently, resulting in the formation of?

• Stable, Inactive & Active Metabolites.

• and sometimes reactive and potentially toxic metabolites.

The balance between these Phase 1 & 2 Metabolic pathways will determine the overall?

• Biological Response to the Drug

Phase 1 reactions generally…?

• Precede Phase 2 but not always

During Phase 1 reactions the chemical is converted to a more polar derivative by either?

• introducing or unmasking a functional group

Phase 1 Reactions Occur Via ?

• oxidation, reduction or hydrolysis.  

The majority of oxidation reactions are catalysed by the?

• cytochrome P450

• (often referred to as CYP)

CYP is mainly involved in metabolizing?

• Foreign Compounds.

How are CYP Enzymes classified?

• Families

• Subfamilies

• Individual Enzymes

How are CYP Enzymes Families classified?

• Families are Identified by a Number E.G CYP1 = Family 1

• CYP1, CYP2, CYP3

How are CYP Enzymes Subfamilies classified

• Subfamilies are identified by a Letter.

• E.G CYP1 + A

• = CYP1A

individual enzymes: Identified by a?

• By a number after the Subfamily

• E.G CYPA1 = A

• = CYPA1A

Oxidation of foreign compounds, important for?

• Drug Metabolism & Detoxification

The reactions catalysed by CYP require the drug?

• NADPH

• The overall reaction is shown below:

  Drug +NADPH +H⁺+O₂ →Drug-OH+NADP+H₂O

Reduction reactions are much less?

• Less common than Oxidative Reactions

Reduction reactions are catalysed either via?

• microsomal or cytosolic reductases.

Ester and amide bonds are subject to?

• Hydrolysis reactions

esterases and amidases, These enzymes are found in the?

• Cytosol and Various Tissues

• Esterases is also found in Plasma

Local anaesthetics, for example are inactivated by?

• Hydrolysis

Phase 2 reactions are conjugation reactions that involve the addition of a?

• endogenous (polar) molecule which makes the drug metabolite

• more water soluble and so more easily excreted in the urine or bile

The conjugates formed are usually?

• Inactive

Phase 2 reactions generally take place in the?

• Liver but also can Occur in the Kidneys