topic 16 - metabolism, excretion and formualation Flashcards
drug metabolism concepts
chemical reactions that occur in the body to maintain life
allow organisms to grow and reproduce, maintain their structures, and respond to their environments
divided into 2 categories:
Catabolism breaks down organic matter
Anabolism uses energy to build up or construct components of cells such as proteins and nucleic acids.
drug metabolism concepts pt 2
Metabolism = Catabolism (breaking down of substances) + Anabolism (building up or synthesis of substances)
Drug metabolism: catabolism = break down of drug molecules + anabolism = modification with the addition of water solubilizing groups
Drugs are synthesized in laboratory
not an endogenous event but a xenogenous one
originating outside the organism
Lipid soluble drugs require more metabolism to become polar, ionizable and easily excretable which involve both phase I and phase II mechanisms.
definition of drug metabolism
Definition: Any chemical alteration of a drug by the living system
purpose of drug metabolism
Purpose: To enhance water solubility (hydrophilicity) and hence excretability.
Main site - liver (before the drug has become available for use, is called the first pass effect) involves cytochrome p450
Other sites include the gastrointestinal wall, kidneys, blood.
Factors affecting metabolism?
The structure of a drug influences its physicochemical properties.
The more complex the structure, the more the potential sites for metabolism.
Blocking/altering sites of metabolism can improve availability of the drug.
phase 1 of drug metabolism
Phase I -oxidative transformations
Production of a new polar groups are introduced or exposed by oxidation, reduction, hydrolysis.
Oxidations are catalysed by the enzyme cytochrome p450 (CYP).
Membrane bound enzyme (on endoplasmic reticulum)
Two most important enzymes being CYP3A4 and CYP2D6.
Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome p450 enzymes.
Oxidation
Aliphatic or aromatic hydroxylation
Reduction
Nitro reduction to hydroxylamine/amine
Hydrolysis
Ester or amide to acid and alcohol or amine
phase 2 of drug metabolism
Phase II – conjugation
Original drug or its metabolite – made more polar by conjugation reactions.
Original drug or its metabolite – made more polar through conjugation reactions catalysed by transferase enzymes. The resulting conjugates are usually inactive
Addition of a to the molecule
Conjugation involves
Glucuronide formation – Glucuronyl transferase
sulphate – sulfotransferase
glutathione derivatives
) Glucuronidation
Carboxylic acid, alcohol,
phenol, amine
(ii) Sulphation
Alcohol, phenol, amine
(iii) Glutathione conjugation (gly-cys-glu)
Halogenated-compounds and epoxides
what is a prodrug?
Codeine is a prodrug: an inactive compounds converted to an active compound in the body
This usually happens through metabolic processes, but can occur by simple chemical reaction.
Prodrugs are used to improve ADME properties
Improve membrane permeability by reducing polarity:
Improve prolong drug activity by releasing the active compound slowly:
excretion (elimination)
Elimination: the irreversible transfer of a drug from the systemic circulation
Major routes of elimination:
Metabolism
Renal excretion (for free drug, i.e. low logD)
Biliary excretion
Also lungs, sweat etc.
how is urine formed?
Tubular Reabsorption
The removal of water (~99%) and solutes from the filtrate
The water and solutes return to the blood via the peritubular capillaries
Tubular Secretion
Transport of excess solutes and wastes from the peritubular fluid into the tubular fluid
what are nephrons?
Nephrons are the functional unit of the kidney, with 1,000,000 nephron in each kidney. Each nephron consists of a glomerulus (a bundle of tiny capillaries) and a system of tubules.
renal excretion (elimination) of drugs
- All unbound drug in plasma is filtered in the glomerulus. Only significant for very polar compounds, log P < 0.
- Some compounds are actively secreted into urine along the proximal tubule.
- Un-ionised drug can undergo passive reabsorption from urine into blood along the length of the nephron (net excretion may be zero).
- Drug that is bound to plasma proteins is not filtered.
solubility - polymorphs
A particular problem can be polymorphism: one compound can crystallise in a variety of ways. Each version will have different solubility.
> 60 forms of Lipitor known:
~1/3 drug molecules have known polymorphs
Considerable work is required to make sure that the right crystal form is obtained.
formulation
Even for one route of administration there can be a range of possible dosage forms:
Liquid
Solutions, syrups, suspensions, emulsions
Semisolid
Creams, ointments, gels
Solid
Tablets, capsules, suppositories, transdermal patches
Getting this right will be critical for clinical testing and marketing of a drug
formulation pt 2
In each case the active pharmaceutic ingredient (API) – the drug itself – is combined with excipients – other ingredients which improve its deliver quality
Fillers: bulking agents which make a small quantity easer to handle (e.g. starch, calcium salts, sugars such as lactose)
Lubricants/antiadherents: reduce friction during manufacturing (e.g. magnesium stearate)
Binders: polymers used to turn powders into granules and pills (e.g. gelatin, polyethylene glycol, polysaccharides)
Preservatives: usually anti-oxidants (e.g. vitamin C, citric acid) or antifungal/bacterials (parabens)
Flavourings: sweeteners (usually artificial) or others to mask unpleasant taste
Coatings: also protect from unpleasant taste, usually hydroxypropyl methylcellulose. Capsules are coated in gelatin. All dissolve in the stomach.
Vehicles: in liquids and gels, the rest of the liquid: water, mineral oil, DMSO
