Drug metabolism Flashcards
What is drug metabolism and what is its main purpose?
The biotransformation of pharmaceutical substances in the body so that they can be eliminated more easily. This happens in the liver.
What are xenobiotics?
Foreign substance to the body e.g. drugs, plant metabolites, food additives etc.
1. Water soluble are easily excreted in urine.
2. Lipophilic: some are not easily excreted and are deposited in adipose tissue or have to be metabolised to water soluble products.
Discuss the 2 phases of liver detoxification.
Phase 1: compound is oxidised, reduced, hydrolysed then excreted.
Phase 2: compound is conjugated to hydrophilic molecule then excreted.
*some compounds go through both phases
What is liver activation?
Compound goes through phase 1 but instead of detoxification & excretion, we have an inactive drug that is transformed into an active metabolite/ toxin.
What type of oxidation reaction happens in phase 1 reaction?
Monooxygenase (enzymes) reactions that require cytochrome p450.
What is cytochrome p450?
They’re electron carriers that have a porphyrin structure (haem group with fe3+).
Discuss the Cytochrome P450 nomenclature.
- Name derived from their absorption spectrum.
It has a max frequency of 450 nanometres in complex with carbon monoxide. - It has 18 families, 43 subfamilies and 57 genes.
What is cytochrome p450’s primary role?
- Hormone synthesis & breakdown
- Metabolism & detoxification of compounds after ingestion
- Drug biotransformation & drug metabolism
Discuss the control of cytochrome p450?
- Inhibition:
- p450 2B6 - orphenadrine, thiotepa, ticlopidine
- p450 2e1- Disulfiram, ritonavir. - Induction:
- p450 2B6 - Phenobarbitone, phenytoin, primidone, Rifampin
- p450 2E1- ethanol, isoniazid. - Genetic variation (from person to person)
- Genetic variants exist with a frequency of at least 1%
- Lack of functional activity = Specific drug toxicity or Inactivity of pro-drug
Discuss drug interactions with CYP P450: activation.
- Some drugs activate P-450 e.g. Phenobarbitone (sedative) induces CYP2C9.
-For patients on warfarin, may lead to low levels of warfarin. – Increased risk of clotting. - Warfarin is metabolised by multiple cytochromes including CYP2C9 and CYP3A
Discuss drug interactions with CYP P450: inhibition.
- Some drugs inhibit P-450, leads to increased levels of other drugs.
- E.g. patients on warfarin taking the anti-fungal ketoconazole have increased warfarin levels as ketoconazole inhibits CYP3A4. Increased risk of bleeding.
What is CYP3A4?
- CYP3A4 is the major isoform in human liver, it oxidatively metabolises > 50% of drugs.
What is the fruit that interacts greatly with drugs?
-Grapefruit juice naturally contains CYP3A4 inhibitors (furanocoumarins).
-More than 85 drugs that may interact with the fruit 45 with have serious side-effects (death, AKI).
- Simvastatin combined with a 200 ml glass of grapefruit juice once a day for three days, produces a 330 per cent rise in the systemic concentration of the drug.
Recall the types of reaction involved in phase I drug metabolism.
- Introduction of functional groups; -OH, -NH2, -COOH
- Prepare substance for conjugation (Phase II metabolism)
- Reactions: Reduction, Hydrolysis, Oxidation
- Oxidation: most common phase I reaction type.
Phase I Reactions – Reduction.
- Chloramphenicol is a broad-spectrum antibiotic which is reduced by nitro-reductase.
*Reduction implies the addition of two hydrogens to the molecule nitro is the chemistry name given to the –NO2 functional group.
Phase I Reactions – Hydrolysis.
- Aspirin at pH 7 is hydrolysed by esterases to salicylate and acetate.
*Hydrolysis implies the addition of water (H2O) to the molecule resulting in the breaking of the molecule into two parts.
Phase I Reactions: Oxidation.
- Many oxidation reactions are catalysed by the mixed function oxidase (MFO) system – (Cytochrome P450, NADPH & molecular O2).
- Reaction: RH + O2 + 2H+ + 2e- = ROH + H2O (where R is the drug)
- Oxidation can occur by: Hydroxylation, Dehydrogenation, Oxidative dealkylation.
Phase I Reactions: Hydroxylation.
- Addition of “OH” group.
- E.g. RH + O2 + NADPH + H+ = ROH + H2O + NADP+
- Take place mainly on the endoplasmic reticulum of liver cells.
- Lipophilic → hydrophilic compounds → more readily excreted.
Example of hydroxylation reaction: lidocaine.
Metabolism involves addition of an - OH group as a first step via P450, NADPH, O2.
What is Cytochrome P450’s Mechanism of action?
- Incorporates one atom of molecular oxygen into substrate creating an -OH group
- The other O is reduced to water
- NADPH provides reducing equivalents.
- Hydroxylation may activate/inactivate a drug or make a drug more soluble
- Or act as a site for conjugation (Phase II) e.g. glucuronidation
Describe the complete metabolism of ethanol.
This is a Phase I reactions via dehydrogenation = Elimination of hydrogen (H2).
Why is a deficiency in aldehyde dehydrogenase important in ethanol metabolism?
- Leads to Acetaldehyde accumulation
- Symptoms: vasodilation, facial flushing & tachycardia.
Explain the mechanism of action of disulfiram (treatment for alcohol abuse).
- Helps to maintain abstinence
- Highly lipid soluble (accumulates in adipose tissue) & has 80% bioavailability after an oral dose.
- MOA: Irreversibly inhibits the oxidation of acetaldehyde by competing with cofactor NAD.
- Causes a 5-10 fold ^ in acetaldehyde concentration which produces unpleasant side effects.
Phase I Reaction: oxidative dealkylation.
Removal of alkyl group from an organic compound. E.g. metabolism of Codeine.
1. Oxidative dealkylation: alkyl group of codeine is oxidised to an aldehyde.
2. 10% of codeine converted to morphine
3.The analgesic effect of codeine due to its conversion to morphine.
