Drug Metabolism Flashcards
Cimetidine
Inhibits CPY450
Omeprazole
Inhibits CYP450 reducing anti-platelet effects on clopidogrel (which is a pro-drug) decreasing activation
Metronidazole
Metabolised by CYP450
- Dose reduced in patients with serious liver disease
- Inhibits acetaldehyde dehydrogenase (avoid alcohol)
Warfarin
if metabolism is inhibited, warfarin increases and increases your risk of bleeding
Clarithromycin
Inhibits CYP450
Statins
Reduced metabolism of statin, increases statin concentration leading to myopathy (muscle toxicity)
Intestinal transporters
Drug passes intestinal tract and comes in contact with:
- OATP (organic ion transporter protein) - facilitate the cellular uptake of small hydrophilic organic anions in order to be excreted via the urine
- expressed in kidneys and liver
- P-gpmdr (P-gllycoprotein multi drug resistance) protein - ATP dependent efflux pump that pumps foreign stuff out of the cell into the intestinal lumen. It is found in the apical enterocytes
Enterohepatic circulation
Trapped in a circulation when bile secreted in duodenum reabsorbs back to liver and bile again
- It can enter systemic circulation or it can be excreted too
What is metabolism
It is the elimination and termination of their biological activity through enzymatic process converting a non-polar lipophilic into a more polar hydrophilic
Concept of metabolism
- Some metabolise in intestinal wall or due to plasma cholinesterase
- Water soluble drugs do not enter cell and are excreted in urine
- Lipid soluble drugs reach hepatocytes
- Most metabolites produced are generally inactive or less active
- Some metabolites may generate toxicity
Phase 1 metabolism
- Introduces or unmasks a functional group making it more polar i.e. NH2, OH and SH
- Reduction, Oxidation, Hydroxylation
- May result in less pharmocological active drug/more active(pro-drug)/toxic metabolite
- May be excreted in urine or undergo phase 2
Phase 2 metabolism (conjugation)
Covalent linkage between function group on phase 1 metabolite and endogenous substrate -i.e. sulfate, methyl, acetyl, glycyl, glucuronyl, glutamyl
- High polar compound formed
- Excreted in urine or faeces
Inducers
BARBITURATES, CARBAMAZEPINE, ALCOHOL, GLUTETHIMIDE, GRISEOFLUVIN, MEPROBAMATE, PHENYTOIN, RIFAMPICIN, SULPHINPYRAZONE
- Increases enzymatic activity and decreases drug potency
St.Johns wort
Inducer of CYP3A4 - increases cyclosporine elimination which is a problem for transplant rejection
Paracetamol Metabolism
- Conjugation with glucuronic acid forming glucuronide moiety (45-55%) - NON TOXIC
- Conjugation with sulfuric acid forming sulfate moiety (20-30%) - NON TOXIC
- Oxidised to form N-acetyl p-benzoquinone imine (NAPQI) (<15%) - TOXIC
- Can be toxified by conjugation of imine with
glutathione forming cysteine and mercapturic acid
- Can be toxified by conjugation of imine with
Alcohol/phenobarbital and paracetamol
They are both inducers of liver microsomal enzymes which increase the susceptibility of increasing the formation of toxic metabolite
Treating paracetamol overdose
Acetylcysteine (N-acetylcysteine, parvolex, NAC) reverse the effects if taken in the first 8 hours of an overdose. May be effective up to 24 hours.
Grapefruit juice
- Inhibits CYP3A4 and delays cyclosporine elimination
- Leads to cyclosporine nephrotoxicity
- Reduces plasma concentration of aliskiren and bilastine by affecting absorption and bioavailibility
- Blocks inhibition of OATP1A2- bilastine is a substrate for this transporter meaning it is removed by excretion
Age
- Limited ability to metabolise until age 10/12
- Children more susceptible to liver damage from substances that enter blood circulation
- In children under 1, microsomal enzymes not fully developed so drugs metabolise slowly
- Foetal/neonatal perid - UGT expression significantly reduced and is only acheived after 24 months
Elderly have reduced liver size, reduced hepatic blood flow and reduced enzyme activity leading to decreased metabolism
How does polymorphism result
- Gene deletion - No enzyme
- Single gene copy - Unstable enzyme, normal enzyme, altered substrate specificity
- Gene duplication/multiplication - Higher enzyme levels
Genetic polymorphism
- Concerns N-acetyltransferase, glucose-6-phosphate dehydrogenase and CYP450
- Patients classified into extensive, intermediate and poor metabolisers
G6PD
Cytosolic enzyme in pentose phosphate pathway
It protects red blood cells from harmful byproducts that may accumulate
- Deficiency of this enzyme causes hemolytic aneamia
- Deficiency symptom triggers - certain painkillers, antibiotics, antimalarial drugs
N-acetyltransferase
It is a phase 2 conjugating liver enzyme catalysing N-acetylation and O-acetylation
It is possible to separate drugs into fast acetylators and slow acetylators
- ISONIAZID, HYDRALAZINE,PROCAINAMIDE AND SULPHASALAZINE
Absorption and bioavailability
Drug passes intestinal tract
Enterocytes contain OATP (Organic anion transport proteins)
There are efflux transporters such as P-Gpmdr (P-glycoprotein multidrug resistance) protein found in the apical layer of enterocytes which kicks drugs out
This bring them back into the intestinal lumen
Drugs also run through inactivating enzymes found in gut wall and liver (first pass metabolism)
Enzyme inhibitors
Cimetidine, erythromycin, clarithromycin, diltiazem, itraconazole, ketoconazole, ritonavir, verapamil, grapefruit, quinolone, sodium valproate, allopurinol
Slow down metabolism and increase action of drug which is prolonged
Grapefruit inhibits CYP3A4 and delays cyclosporine elimination leading to nephrotoxicity
Paracetamol metabolism
3 different pathways
- 45-55% conjugates with glucuronic acid forming glucuronide which is non-toxic
- 20-30% conjugates with sulfuric acid to form sulfate which is non-toxic
- <15% is oxidised to form NAPQI (N-acetyl-p-benzoquinone imine)
- This can be detoxified by conjugation of imine with glutathione to form cysteine and mercapturic acid
