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Transcript of Drug Metabolism
parent entitiy resulting in its eventual removal from the body... ...which may result in the bioactivation or inactivation
of a parent drug making it more or less potent An Overview of Drug Metabolism There are a variety of Phase I reactions
that are not catalysed by CYP450: Hydrolytic enzymes Epoxide hydrolase Ethanol metabolism Are present in the blood, liver, kidneys and other tissues. Acetylsalicylic acid is hydrolyesed by cholinesterase and other esterases present in the serum. They have a similar mechanism to peptidases. Serine, Threonine, Cysteine peptidases and esterases
form a covalent intermediate in the active site Choline esterase contains a Glu-His-Ser catalytic triad Alcohol consumption far exceeds that of any other
drug when judged on a molecular basis. It is rapidly absorbed through the stomach and the majority is metabolised by the liver CYP450 are membrane bound monooxygenases in the smooth endoplasmic reticulum. They form a hydrophobic area which attracts hydrophobic molecules. Usually enzymes develop over time to have exquisite substrate specifity but not the CYPs. For example, CYP3A4 is known to metabolise over 120 different drugs The molecule then undergoes a reaction in the p450 enzyme to make it less hydrophobic to expel it from the active site and let the process begin again. So, what is a CYP? They are heme containing enzymes which, when reduced and complexed with CO, have a characteristic absorbance at 450nm (hence the name P450) CYPs are membrane bound proteins and must be associated in a complex with P450 reductase which relies on NADPH. NADPH supplies the electrons needed for the reaction, without it, CYP450 wouldn't work. The active site of the CYP is made up of hydrophobic residues. The use of double-single-double bonds all around makes it a big conjugated system and the overlap of p orbitals in the same plane gives it a planar structure. These reactions prepare functionally activated compounds for excretion in the bile or urine. Involves the conjugation of the Xenobiotic with one of a variety of different compunds. a chemical which is found in an organism but is not normally produced or expected to be present in it This results in a pharmacologically inactive soluble compound. The reactions are catalysed by a variety of different enzymes Four main reaction types: Sulphation Methylation Glutathione Conjugation Involves the addition of SO3- to the drug and is the major conjugation pathway for phenols and can occur for alcohols, amines and occassionaly thiols This requires a energy rich donor compound 3'-phosphoadenosine-5'-phosphosulfate aka PAPS Carboxylesterases hydrolyse esters and some amides.
Amides are more stable than esters. The more lipophilic
the amide, the better the substrate. Epoxide hydrolase is responsible for the hydration of epoxides. They catalyse nucleophilic addition in the presence of water Usually there are low levels of ethanol in the blood. In large amounts, circulating ethanol can cause unpleasent effects:
Panic/distress Epoxides are often generated by CYP450 activity. They are very reactive due to the charged oxygen and the strain the bonds are under. They react with DNA & proteins and are usually carcinogenic Key Points! Key Points! Tripeptide glutathione (GSH) contains Glu-Cys-Gly. Many drugs are metabolised to toxic electrophiles. GSH is conjugated with toxic electrophiles. This includes epoxides, haloalkanes, nitroalkanes, alkenes, aromatic halo- and nitro-compounds Key Points! Many drugs metabolising enzymes
are polymorphic due to polymorphisms.
A SNP causes a change in a single nucleotide. Polymorphism Drug-Drug Interactions Age Gender Disease and Drug Metabolism Key Points! Some drug interactions are able to enhace
or inhibit the activity of CYP450 The very young and the elderly exhibit
diminished drug metabolism Men and women older than 65-70 years have significantly decreased drug metabolism
Diminished enzyme induction
Are on many drugs, around 5, and so there is the possiblity of drug-drug interactions First observed in rats. Male rats metabolised drugs faster than females The gender effect may be related to sex hormones. The sex difference in metabolism is important in animals but of less significance in man. The frequency of drug induced hepatotoxicity is higher in females - Halothane, Isoniazid, Nitrofurantoin, Flucloxacillin Disease of the liver generally results in decreased drug metabolism capacity A drug may be metabolised in three ways: 1) via Phase I metabolism that use CYP450 enzymes 3) and via Phase II metabolism reactions 2) via Phase I reactions that DO NOT Key Points! Phase II
metabolism Phase II metabolism reactions are the conjugation of the functional group with a less reactive species and so are called conjugation reactions It is a detoxification step which generates compounds that are inactive and can be readily excreted due to the formation of a large sugar group This is done via: Glucoronidation Methylation Sulfonation and through the
addition of Glutathione Phase I metabolism
using CYP450 enzymes The reaction produces or uncovers a chemically reactive
functional group which prepares the drug for phase II metabolism. 1) O-Dealkylation Phase I metabolism reactions are functionalisation reactions,
they make the group more polar through oxidation. add one oxygen to the drug There are 4 types of re-arrangement reactions: we shall discuss this
in detail later on 3) S-Dealkylation These reactions are called re-arrangement reactions and are carried out via CYP450 by MONOXYGENASES 4) Epoxydation 2) N-Dealkylation Conjugation with a sugar - glucuronic acid The addition of SO3- to the drug Nucleophilic addition of thiolate anion to electrophilic centres in xenobiotics Use of the high energy co-factor SAM Glucuronidation Is the conjugation of the drug with sugar Glucuronic acid transferred from high energy phosphate compound UDP-GA to electron rich atom, N, O or S Rich source in the liver Highly soluble in water
pKa of the acid 3-4 Glucuronic acid Not fully 'metabolically competent'
Virtually no Phase II metabolism (chloramphenicol toxicity due to poor glucuronidation - Gray Baby Syndrome)
Limited Phase I enzyme activity Elderly Very Young - CYP3 activity only e.g. Codeine metabolism
- Capacity increases during development Drug metabolism involves two phases Phase I reactions generate a reactive functional group Phase II reactions are conjugation reactions which result in the eventual elimination if the drug The major organ involved in drug metabolism is the liver 1) Hydrolysis is a key Phase I metabolic reaction involving esterases and amidases 2) Expoxidation can lead to DNA damaging metabolites 3) Epoxidase enzymes form diols which can then undergo Phase II reactions 4) Ethanol metabolism involves two dehydrogenases (oxidations) 5) Inhibition of aldehyde dehydrogenase leads to side effects that can be utilised for alcohol treatment Other oxidases Xanthine oxidase Metabolism of drugs containing xanthine
e.g. caffeine, the bronchodilator, theophylline & theobromine. Enzyme oxidises drugs to uric acid derivative Alkyl hydrazine oxidase Metabolism of carbidopa, a drug used in combination with levadopa to treat Parkinson’s disease Oxidation reaction, but mechanism not fully understood CYPs are working constantly to detoxify Hydrophobic active site promotes reaction and removal of substrate Enzyme complex with reductase Catalystic cycle involves oxidation of iron Phase 2 reactions involve conjugation of the functionally active drug Generally result in a less reactive, more polar compunds that are readily excreted Not all conjugates are less reactive or easily excreted 1) Disease of the liver generally results in decreased drug metabolism capacity 2) Decreased enzyme acitivity is in part responsible for changes in drug metabolising capacity of the liver 3) Genetic variation can affect metabolism and response to drugs 4) Genetic tests can be developed and applied to ensure patients recieve an appropiate dose of the drug 5) Drug-drug interactions and age are important in considering the metabolism and potential for side effects of drugs