Basic principles of drug metabolism, P450S and excretion Flashcards
Describe the role of the liver in pharmacokinetics.
- Liver is prime site of drug metabolism
- Ultimate elimination organ
- Responsible for pre-systematic
elimination (First-Pass Effect) - Most drugs are metabolised in the liver
- Metabolism primarily involves
Cytochrome P450 enzymes (CYP450)
located in hepatocytes
Describe the stages of drug metabolism.
- Enzymatically mediated modification of the chemical structure of a molecule
- Primary ‘purpose’ is to make fat soluble chemicals water soluble
- Removal of drug from the systematic circulation
What is meant by drug clearance?
Lipid soluble drugs which are poorly excreted in the urine are stored in adipose/circulate until they are converted to more water soluble metabolites which are more readily excreted in the urine.
Describe the pathway of drugs administered as IV, TD or SC.
- Enter systemic circulation directly and reach target organs before hepatic modification
Describe the absorption of oral drugs.
- Absorbed in GI tract and delivered via portal vein to liver; allows liver to metabolise drugs before systemic circulation (first-pass effect)
What are the bioavailability implications of oral drugs?
Oral drug with extensive first pass metabolism needs administration at larger dose than equivalent IV formulation.
Describe the dose of drugs low first-pass effect compared to IV.
Require similar or only slightly higher oral doses.
Where does metabolism occur?
Primarily the liver but also:
- lung
- kidney
- intestine
- adrenal
- skin
- brain
Describe phase 1 reactions of metabolism.
- Convert parent compound into a chemically active more polar (hydrophilic)
metabolite by adding or unmasking functional groups (-OH, -SH, -NH2 , -COOH, etc.) - May be sufficiently polar to be excreted readily
Describe phase 2 reactions in metabolism.
- Occur at chemically reactive sites, with phase I reaction normally preceding
- Conjugation with endogenous substrate to further increase aqueous solubility;
(glucoronide, sulphate, acetate, amino acid etc.) - Metabolites are usually inactive
Describe phase 3 - transmembrane transport of metabolism.
- Efflux of metabolites and sometimes unchanged parent molecule into bile and urine
- Anti-porter activity (e.g. P-glycoprotein, multi-drug resistance)
Describe the oxidation reactions in phase 1.
- Oxygen incorporated into drug
- Oxidation causes loss of part of drug
What is meant by elimination?
- Any process involved in the excretion of drugs from the body/removal of drugs from the body.
What are the major elimination routes?
Kidney and liver - drugs get excreted either directly or as metabolites
What are the minor elimination routes?
- Exhalation
- Sweat
- Saliva
- Breast milk
