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Phase 1 Drug Metabolism Biology

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The whole scope of biochemical procedures that occur within an being, Metabolism consists both of constructive metabolism and katabolism ( the buildup and dislocation of substances, severally ) . The biochemical reactions are known as metabolic tracts and affect enzymes that transform one substance into another substance, either interrupting down a substance or constructing a new chemical substance. The term is normally used to mention specifically to the dislocation of nutrient and its transmutation into energy.

The liver is the chief site of drug metamorphosis.

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Although metamorphosis typically inactivates drugs, some drug metabolites are pharmacologically active sometimes even more than the parent compound. An inactive or decrepit active substance that has an active metabolite is called a pro-drug, particularly if designed to present the active mediety more efficaciously.

Drugs can be metabolized by oxidization, decrease, hydrolysis, hydration, junction, condensation, or isomerisation, whatever the procedure, the end is to do the drug easier to egest. The enzymes involved in metamorphosis are present in many tissues but by and large are more concentrated in the liver.

Drug metamorphosis rates vary among patients. Some patients metabolise a drug so quickly that therapeutically effectual blood and tissue concentrations are non reached, in others, metamorphosis may be so slow that usual doses have toxic effects. Individual drug metamorphosis rates are influenced by familial factors, coexisting upsets ( peculiarly chronic liver upsets and advanced bosom failure ) , and drug interactions ( particularly those affecting initiation or suppression of metamorphosis ) .

For many drugs, metamorphosis occurs in two stages:

Phase I reactions: Which involve formation of a new or modified functional group or cleavage, these reactions are nonsynthetic.

Phase II reactions

Which involve junction with an endogenous substance, these reactions are man-made. Metabolites formed in man-made reactions are more polar and more readily excreted by the kidneys ( in piss ) and the liver ( in gall ) than those formed in nonsynthetic reactions. Some drugs undergo merely stage I or phase II reactions, therefore, phase Numberss reflect functional instead than consecutive categorization.

Phase I Drug Metamorphosis

Phase I metabolism includes oxidization, decrease, hydrolysis and hydration reactions, every bit good as other rarer assorted reactions. Oxidations performed by the microsomal, mixed-function oxidase system ( cytochrome P450-dependent ) is considered individually because of its importance and the diverseness of reactions performed by this enzyme system.

Categorization of Phase I Reactions:








Applications of Phase I Metabolism


Oxidations affecting cytochrome P450 ( the microsomal mixed-function oxidase )

The mixed-function oxidase system found in microsomes ( endoplasmic Reticulum ) of many cells ( notably those of liver, kidney, lung and bowel ) performs many different functionalisation reactions.

CYP 450: The cytochrome P450 ( CYP ) enzyme system consists of a superfamily of haemoproteins that catalyse the oxidative metamorphosis of a broad assortment of exogenic chemicals including drugs, carcinogens, toxins and endogenous compounds such as steroids, fatty acids and prostaglandins. The CYP enzyme household plays an of import function in phase-I metamorphosis of many drugs. The wide scope of drugs that undergo CYP mediated oxidative biotransformation is responsible for the big figure of clinically important drug interactions during multiple drug therapy.

All of these reactions require the presence of molecular O and NADPH every bit good as the

complete mixed-function oxidase system ( cytochrome P450, NADPH-cytochrome

P450 reductase and lipoid ) .

All reactions involve the initial interpolation of a individual O atom into the drug molecule. A subsequent rearrangement and/or decomposition of this merchandise may happen, taking to the concluding merchandises formation.

( I ) Aromatic hydroxylation: This is a really common reaction for drugs and xenobiotics incorporating an aromatic ring. In this illustration the local anesthetic and antidysrhythmic drug, lignocaine, is converted to its 3-hydroxy derived function.

( two ) Aliphatic hydroxylation: Another really common reaction, e.g. pentobarbitone hydroxylated in the pentyl side concatenation.

( three ) Epoxidation: Epoxides are usually unstable intermediates but may be stable adequate to be isolated from polycyclic compounds ( e.g. the precarcinogenic polycyclic hydrocarbons ) . Epoxides are substrates of epoxide hydrolase ( discussed subsequently ) , organizing dihydrodiols, but they may besides spontaneously decompose to organize hydroxylated merchandises or quinones. It has been suggested that epoxide formation is the first measure in aromatic hydroxylation.

( four ) Dealkylation: This reaction occurs really readily with drugs incorporating a secondary or third aminoalkane, an alkoxy group or an alkyl substituted thiol. The alkyl group is lost as the corresponding aldehyde. The reactions are frequently referred to as N- , O- or S-dealkylations, depending on the type of atom the alkyl group is attached to.

( V ) Oxidative deaminization: Amines incorporating the construction -CH ( CH3 ) -NH2 are metabolised by the microsomal mixed-function oxidase system to let go of ammonium ions and leave the corresponding ketone. As with dealkylation, oxidative deaminization involves an intermediate hydroxylation measure with subsequent decomposition to give the concluding merchandises.

The merchandise of the oxidative deaminization of EPI or NE is 3,4-didydroxyphenylclycoaldehyde ( DOPGAL ) . DOPGAL is capable to decrease to the corresponding intoxicant ( 3,4-dihydroxyphenylethylene ethanediol, DOPEG ) or oxidization to the corresponding carboxylic acid ( 3,4-dihydroxymandelic acid, DOMA ) , the latter being the major tract.

( six ) N-oxidation: Hepatic microsomes in the presence of O and NADPH can organize N-oxides. These oxidization merchandises may be formed by the mixedfunction oxidase system or by separate flavoprotein N-oxidases. The enzyme involved in N-oxidation depends on the substrate under survey. Many different chemical groups can be N-oxidised including aminoalkanes, amides, imines, hydrazines and heterocyclic compounds.

( seven ) S-oxidation: Phenothiazines can be converted to their S-oxides ( sulfoxides ( S?O ) and sulfones ( ?S?O ) ) by the microsomal mixed-function oxidase system.

( eight ) Phosphothionate oxidization: The replacing of a phosphothionate S atom with O is a reaction common to the phosphothionate insect powders, e.g. parathion. The merchandise paraoxon is a powerful anticholinesterase and gives the powerful insecticide action every bit good as the toxicity in worlds.

Oxidations non catalysed by cytochrome P450 ( Non-Microsomal )

A figure of enzymes in the organic structure non related to cytochrome P450 can oxidise drugs.

( I ) Alcohol Oxidation by Alcohol dehydrogenase: This enzyme catalyses the oxidization of many intoxicants to the corresponding aldehyde and is localised in the soluble fraction of liver, kidney and lung cells. This enzyme uses NAD+ as co-factor and is a true dehydrogenase.

( two ) Aldehyde oxidization: Aldehydes can be oxidised by a assortment of enzymes involved in intermediary metamorphosis, e.g. aldehyde dehydrogenase, aldehyde oxidase and xanthine oxidase ( the latter two being soluble metalloflavoproteins ) .

( three ) Oxidation by Xanthine oxidase: This enzyme will metabolize xanthine-containing drugs, e.g. caffeine, Elixophyllin and theobromine, and the purine analogues to the matching uric acerb derived function.

Metabolic Reduction

( I ) Azo- and nitro-reduction can be catalysed by cytochrome P450 ( but can besides be catalysed by NADPH-cytochrome P450 reductase ) .

( two ) Ringing cleavage: Epoxides can be converted back to the parent hydrocarbon, e.g. benzo ( a ) anthracene- 8,9-epoxide whereas some heterocyclic compounds can be pealing cleaved by decrease.

( three ) Reductive defluorination: Fluorocarbons of the halothane type can be defluorinated by liver microsomes in anaerobiotic conditions.

Metabolic Hydrolysis

Esters, amides, hydrazides and carbamates can readily be hydrolysed by assorted enzymes.

( I ) Ester hydrolysis: The hydrolysis of esters can take topographic point in the plasma ( nonspecific acetylcholinesterases, pseudocholinesterases and other esterases ) or in the liver ( specific esterases for peculiar groups of compounds ) . Procaine is metabolised by the plasma esterase, whereas pethidine ( Demerol ) is merely metabolised by the liver esterase.

( two ) Amide hydrolysis: Amides may be hydrolysed by the plasma esterases ( which are so non-specific that they will besides hydrolyze amides, although more easy than the corresponding esters ) but are more likely to be hydrolysed by the liver amidases. Ethylglycylxylidide, the N-deethylated stage 1 merchandise of lignocaine, is hydrolysed by the liver microsomal fraction to give xylidine and ethylglycine.

( three ) Hydrazide and carbamate hydrolysis: Less common functional groups in drugs can besides be hydrolysed, such as the hydrazide group in INH or the carbamate group in the antecedently used hypnotic, hedonal.

Factors Affecting Metamorphosis

Many factors can impact liver metamorphosis, such as:

In aging, the Numberss of hepatocytes and enzyme activity diminutions.

Diseases that cut down hepatic blood flow like bosom failure or daze can besides cut down the metabolic potency of the liver.

Besides the usage of other drugs every bit good as dietary and environmental factors can act upon liver metabolic map.

Metamorphosis can besides be altered due to a familial lack of a peculiar enzyme.

Differences in metamorphosis that consequence from functional familial polymorphisms can be accommodated by cognizing the frequence of different genotypes, and by modifying either the enzyme copiousness ( void allelomorphs, for illustration, in the instance of CYP2D6 ‘poor metabolizers ‘ ) or the intrinsic enzyme activity ( for illustration, CYP2C9 discrepancies ) . Data on developmental alterations in the copiousness and activity of different CYPs can besides be incorporated into the theoretical accounts to foretell hepatic clearance in newborns, babies and kids.


Metamorphosis is the dislocation of Drugs inside the organic structure, to disenable their activity, organizing inactive metabolites, nevertheless some drugs are either non affected by metamorphosis or activated by it, some even form toxic metabolites Examples:

Imipiramine non affected by metamorphosis:

Paracetamol produce Toxic Metabolite

Metamorphosis occurs in two stages, Phase I Metabolism, and Phase II Metabolism.

Phase I Metabolism converts the drug into metabolite by formation of a new functional group or modifying it, while stage II Metabolism or reactions involve junction with autochthonal substance.

Phase I Reactions Include:

Oxidation, decrease, hydrolysis and hydration reactions, and other rare assorted reactions.

Oxidation can be divided into Microsomal or not Microsomal harmonizing to whether it involves mitochondrial CYP 450 enzymes.

Oxidation involves:


Aromatic Hydroxylation, Aliphatic Hydroxylation, Epoxidation, Dealkylation, oxidative deaminization, N- oxidization, S-oxidation and Phosphothionate oxidization.


Alcohol Oxidation by Alcohol dehydrogenase, Aldehyde Oxidation and Oxidation by Xanthine oxidase.

Decrease involves: Azo- and nitro-reduction, Ring cleavage, Reductive defluorination

Hydrolysis involves: Ester hydrolysis, Amide hydrolysis, Hydrazide and carbamate hydrolysis

Cite this Phase 1 Drug Metabolism Biology

Phase 1 Drug Metabolism Biology. (2017, Jul 15). Retrieved from https://graduateway.com/phase-1-drug-metabolism-biology-essay/

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