ADME part 2 Flashcards
What typically results from metabolism of a drug?
A more polar metabolite which is often inactive and/or less likely to diffuse through cells and reach receptors and more likely to be excreted in the urine or bile
What are the unusual results of drug metabolism?
In the case of prodrugs there can be promotion of activity by metabolism
A few drugs will have metabolism not change their activity (such as diazepam to nordiazepam)
Some drugs such as paracetamol can produce toxic metabolism
What are examples of prodrugs?
Codeine to morphine
Acetylsalicylate to salicylate
What are the phases of drug metabolism?
Phase one reactions which uncover or add a reactive group making the molecule more susceptible to phase 2 reactions
Phase two reactions which involve conjugation of an endogenous molecule with a drug
Phase one reactions are not always required
What type of chemical reactions make up phase one drug metabolism interactions?
Oxidation, reduction and hydrolysis
What type of chemical reactions make up phase two drug metabolism reactions?
Conjugation with glucuronide, sulphate, amino acids or glutathione as well as acetylation of the drug
What is the most important type of phase one drug reactions?
Oxidation, which is typically performed by the cytochrome p450 dependent mixed function oxidases
What are the cytochrome P450 dependent mixed function enzymes?
A family of closely related oxidative enzymes that are located on the smooth endoplasmic recticulum
CYP1,2 and 3 encode most of the enzymes involved in drug metabolism
How does the microsomal cytochrome p450 monooxygenase reaction occur?
The drug combines with CYP in the oxidised state
The complex is then reduced by a reductase transferring an electron from NADPH
A second electron from the same source serves to reduce oxygen to from an activated oxygen-CYP complex
Complex splits into the oxidised drug, water and the oxidised CYP
What is the overall chemical reaction of drug oxidation by Cytochrome P450?
Drug + O2 + NADPH to Oxidised drug + H2O + NADP+
How are CYPS named?
CY(tochrome)P(450) Number of Family-Letter of subfamily-isoform
What does CYP 1A1/2 metabolise?
Procarcinogens, promutagens, caffeine and theophylline
What does CYP 2C9 metabolise?
R-Mephenytoin, S-Warfarin, omeprazole
What does CYP 2D6 metabolise?
Debrisoquine, spareine, codeine, various beta-blockers and tricyclic antidepressants
What does CYP3A4 metabolise?
Cyclosporine, nifedipine, erythromycin, terfenadine, theophylline, tesosterone
What induces CYP1A1/2?
Benzo(a)pyrenes in cigarette smoke and BBQ meat
What inhibits CYP2D6 metabolism?
Quinidine, fluphenazine and fluoxetine
What inhibits CYP3A4 metabolism?
Quinolones, ketoconazole, erthyromycin and grapefruit juice)
What induces CYP3A4 metabolism?
rifampicin, glucocorticoids and barbiturates
What is the process of induction of CYP enzymes?
There is enzyme synthesis initiated within 24 hours of exposure, increasing over 3-5 days
The effect of this decreases over 1-3 weeks after inducing agent is discontinued
What is the time scale of inhibition of CYP enzymes?
An effect where there is a rapid onset within one day and an exaggerated response to drug with an increased risk of toxicity is observed
What are the compounds that can result in CYP inhibition?
Competitive reversible inhibitors such as cimetidine, ketoconazole, quinolone, oestrogens and grapefruit juice
Heavy metals which complex with CYOSa like lead, cadium and mercury
What is glucuronidation?
A glucuronic acid molecule is added to the drug by a glucuronsyl transferases
What is sulphation?
Addition of a sulphur molecule to the drug by cytosolic sulphotransferase enzyme requiring a co-factor of 3’phosphoadenosine 5’phosphosulphate
What is amino acid/peptide conjugation?
When a drug is combined with (typically) gylcine or glutathione via glutathione S transferases
What is acetylation?
When an N-acetyltransferase adds an acetyl compound, this reaction requires an acetyl coA and is ofent used on sulphonamide drugs