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Biotransformation And Elimination Of Drugs Biology

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    Liver plays a important function in the metamorphosis of a big figure of drugs and toxins. Hepatic drug metamorphosis involves assorted procedures, loosely classified as Phase 1 ( functionalisation ) and Phase 2 ( junction ) . Glucuronidation catalysed by UDP-glucuronosyl transferase ( UGTs ) plays a cardinal function in the Phase 2 metamorphosis of a big figure of drugs every bit good as many endogenous substrates, like hematoidin, steroids etc. , by increasing the hydrophilicity and clearance. UGTs are various enzymes, in footings of wide, yet overlapping substrate specificity, presence of legion isoforms, familial polymorphisms etc.

    Biological systems are recognised to be stereoselective in nature. A big figure of drugs, about 50 % of all marketed drugs exist as either individual enantiomorphs or racemates. Therefore stereoselective behavior of drugs dramas an of import function in drug action every bit good as temperament ( Absorption, Distribution, Metabolism and Elimination ) .

    The purpose of this undertaking is to place the enantio-selectivity of drugs towards glucuronidation by UGT and besides to place whether enantio-selectivity is linked to specific isoforms of UGT. Furthermore, foretelling the enantiomeric behavior of drugs may besides help in rationalizing in-sillico modeling of drug metamorphosis and thereby foretelling metamorphosis of new chemical entities ( NCEs )


    Biotransformation and riddance of drugs from the organic structure involves several different metabolic paths. These metabolic tracts are loosely classified into Phase 1 ( functionalisation ) and Phase 2 ( junction ) drug metamorphosis.

    Phase 1 metabolic tract involves transforming the drug into a more polar functionality, through assorted reactions like, oxidization, decrease, hydrolysis, isomerization and so on depending on the chemical nature of the drug. These reactions are catalysed by enzymes such as: Cytochrome P450, NADPH-cytochrome P450 reductase, acetlycholineestrase etc.

    Merchandise of Phase 1 drug metamorphosis may so move as a substrate for Phase 2 metamorphosis. This stage consists of junction of the drug substrate with endogenous ligands taking to increased mutual opposition, hydrophilicity and thereby riddance of the drug from organic structure through gall or piss. Conjugation reactions include glucuronidation, glycosidation, sulfation, methylation etc. These reactions are catalysed by UDP-Glucuronosyltransferase, UDP-Glycosyltransferase, Sulfotransferase, Methyltransferase severally. Among these, glucuronidation is the most prevailing junction reaction in the organic structure.


    Glucuronidation is the most common reaction in Phase 2 drug metamorphosis. This junction reaction which is catalysed by UDP- glucuronosyl transferase, signifiers about 35 % of all drugs metabolised by junction. This is chiefly due to the copiousness in populating systems of UDP-glucuronic acid, the co-factor for the reaction, every bit good as due to the permeant nature of the enzyme, UDP-glucuronosyl transferases ( UGTs ) .

    The procedure of glucuronidation involves:

    • Formation of co-factor ( UDP-glucuronic acid )
    • Junction of UDP-glucuronic acid with substrate

    The formation of co-factor ( UDP-glucuronic acid )

    This consists of a two measure procedure:

    1. Formation of UDP-glucose: Glucose-1-phosphate is present in high concentrations in about all cells of the organic structure. The first phase of glucuronidation is related to animal starch synthesis through the common intermediate, UDP-glucose. The formation of UDP-glucose occurs by add-on of a Uridine 5′- diphosphate ( UDP ) , a pyrophosphate base in cells, to a molecule of Glucose-1-phosphate. The reaction is catalysed by UDP-glucose pyrophosphorylase enzyme.
    2. Dehydrogenation of UDP-glucose to UDP-glucuronic acid: The above measure is followed by dehydrogenation of UDP-glucose to UDP-glucuronic acid, catalysed by the enzyme UDP-glucose dehydrogenase, in the presence of NAD+ co-factor.

    Junction of the substrate with UDP-glucuronic acid

    Conjugation reaction involves transportation of one I±-D-glucuronic acid mediety from the co-substrate UDP-glucuronic acid ( UDPGA ) , which act as an energy rich intermediate, to organize the glucuronide conjugate of the drug molecule. The reaction is catalysed by UDP-glucuronosyl transferase ( UGT ) enzyme.

    The reaction is found to be a bimolecular nucleophilic permutation ( SN2 ) , whereby the C1 C of glucuronic acid, which is in I±-configuration, during its reaction with the substrate inverts to organize a I-D-glucuronide.. The glucuronide formed is excreted via piss or gall, depending on the chemical nature and molecular weight of the conjugate.

    The full reaction is summarised below:


    Based on the functional group of the substrate molecule, the undermentioned types of glucuronide conjugates may be formed ; O-Glucuronide

    They are formed from Phenols, alcohols, carboxylic acids. O-gulcuronides are chiefly excreted in to bile and may undergo entero-hepatic circulation. Examples of drugs: Morphine, Chloramphenicol, Salicylic acid, Clofibrate.UGT Enzyme


    • N-glucuronide. They are formed by the reaction of UDP-glucuronic acid ( UDPGA ) with aminoalkanes, amides etc. E.g. Sulfanilamide, Cyproheptidine, Dapsone
    • S-Glucuronide. Chemical reaction of thiol groups with UDPGA in presence of UDP-gucuronosyl transferase consequences in S-glucuronides. E.g.Disulfiram, 2-Mercapto benzothiazole
    • C-glucuronide. It is an uncommon metabolic tract that occurs due to the direct fond regard of UDPGA to the C skeleton of drugs. E.g. Sulfinpyrazone.



    UGT enzymes are present in human existences and most other mammals. The enzyme is located in many tissues of the organic structure, largely in liver but besides in kidney, lungs, little bowel, lien, suprarenal glands and tegument, to a lesser extend. Inside the cell, UGTs are bound to the membranes of endoplasmic Reticulum. Most of the Phase 1 metabolic enzymes, including cytochrome P450s, are located in the endoplasmic Reticulum. Therefore endoplasmic Reticulum is regarded as an ideal site for UGT enzymes, as it facilitates glucuronide junction of Phase 1 substrates.

    Structural ASPECTS

    UDP-glucuronosyl transferase enzyme does non incorporate a prosthetic group. The monomeric molecular weight of the enzyme if found to be between 50- 60 kilo Daltons. The protein sequence of the enzyme shows little fluctuations between each single signifier.

    A full length crystal construction of UGTs is yet to be resolved, although crystal construction of the binding sphere for UDP-glucuronic acid in human UGT2B7 has been published ( by Miley 2007 )


    In add-on to being a major enzyme involved in Phase 2 drug metamorphosis, UGT enzymes play a figure of other functions in the organic structure. Many endogenous compounds such as hematoidin, steroid endocrines ( e.g. tetraiodothyronine, liothyronine ) and catechols ( derived from catecholamine metamorphosis ) , act as substrates for UGT enzymes. All these compounds are potentially risky if accumulated in the organic structure.

    Lack of UGT enzyme consequences in hyperbilirubinaemia. Familial diseases like Gilbert ‘s syndrome and Cringler-Najjar ‘s syndrome are associated with familial polymorphisms of UGT cistron. Apart from temperament of endogenous toxins, the enzyme besides catalyses glucuronidation of assorted exogenic chemicals and helps in organic structure ‘s defense mechanism against toxic rules.


    Assorted signifiers of UDP-glucuronosyl transferase ( UGT ) enzymes have been identified with the aid of surveies based on purification, word picture of enzymes, molecular cloning, DNA sequencing etc. About 50 craniate UGTs have been identified among which 19 are found in worlds.

    UGT enzymes are divided in to households and sub-families based on similarity of their amino acid sequences. Two enzymes are in the same household if the similarity of their amino acid sequences is more than 50 % and will be grouped into the same subfamily is similarity is greater than 60 % .


    Divergent development and sequence similarity forms the footing of terminology of UGT enzymes. Name of the enzyme consists of 4 parts:

    Root Symbol. The root symbol ‘UGT ‘ bases for UDP- glucuronosyl transferase.

    Family It is denoted by Arabic figure. E.g. 1, 2 etc

    Sub-family Designated by an upper-case alphabet

    Individual Form An Arabic number is used for alone designation of the single signifier of the enzyme.

    E.g. UGT2B4, UGT1A6

    Mammalian UGTs are divided in to four households: UGT1, UGT2, UGT3 and UGT8. Among these, merely UGT1 and UGT2 catalyses junction of glucuronide and hence are discussed further.

    UGT1A household of enzymes are found to incorporate 9 functional proteins and are coded for by a individual cistron complex located at chromosome 2q37. The cistrons coding for this enzyme have common coding DNAs 2-5 ( part of cistron which codes for the carboxyl end point of the enzyme ) and a variable coding DNA 1. The first coding DNA is responsible for coding the N-terminal sphere of the protein and this explains why the enzymes are substrate specific in malice of have a common C-terminal.

    UGT2 enzyme household, particularly UGT2B plays a critical function in the metamorphosis of xenobiotics and endogenous ligands. Genes coding for UGT2 household enzymes are situated on chromosome 4q13. In the instance of UGT2B sub household, protein sequences at the C-terminal, gives rise to the UDP-glucuronic acid adhering sphere every bit good as aids in anchoring of the protein to membrane of endoplasmic Reticulum.

    UGT2A subfamily is less studied and make non play a important function in systemic metamorphosis. UGT2A1 is present in olfactive epithelial tissues and to a lesser extend in cells of encephalon and lungs. UGT2A2 in liver and little bowel, while UGT2A3 in little bowel, liver and adipose tissue.


    The assorted signifiers of UGT enzymes show tissue specificity in adult male. Majority of these enzymes occur preponderantly in the liver, ( E.g. UGT 1A1, 1A4, 1A6, 2B7 etc ) while some others are found in assorted extrahepatic sites. An illustration is UGT1A10, which is present in the cells of all countries of GI piece of land and hence histories for its broad scope of substrate specificity, from phenol molecules to steroids.


    UGTs show a broad, yet overlapping, scope of specificity towards drugs and endogenous ligands. For illustration, glucuronidation of hematoidin is preferred by UGT1A1 and that of morphia by UGT2B7.


    Several familial polymorphisms in UGTs may take to fluctuations between persons in the ability to glucuronidate drugs and endogenous substrates. Mutants in cistrons coding for UGT1 enzyme household has been identified as the cause for familial hyperbilirubinaemia, characterized by icterus due to high degrees of unconjugated hematoidin in the organic structure.

    Further, several familial diseases- Gilbert ‘s syndrome and Cringler-Najjar ‘s syndrome, may happen due to mutants in cistrons coding for UGT1A1 isoform.


    Study of enzyme dynamicss helps to understand the catalytic mechanism of the enzyme ; function played by the enzyme in metamorphosis every bit good the rate and activity of enzyme. Michaelis Menten equation is used to depict enzyme – substrate interaction and is given by:

    k1 k 2

    E + S ES E + P


    Where E = Enzyme, S = Substrate, P = Product

    Michaelis Constant Km is given by:

    Km = ( k 2 + k -1 ) / k 1

    Michaelis Constant Km is an index of affinity of substrate for the enzyme every bit good as the rate of enzyme activity. The dynamicss of drug metamorphosis can besides be defined utilizing Michaelis Menten equation and may be plotted in a graph of Rate of reaction ( Velocity ) V. Concentration of Substrate. Although non all enzyme substrate reactions are best described by this equation, a typical theoretical account of Michaelis Menten secret plan is shown below:  Here Vmax is the maximal speed of enzyme action. Vmax / Km is an index of the catalytic efficiency of the enzyme.


    Molecules holding the same fundamental law of atoms and sequence of covalent bond, but differ in their 3-dimensional agreement of atoms in infinite are known as stereoisomers. Stereoisomers are classified in to geometrical ( cis/trans ) isomers, enantiomorphs and diastereoisomers. Stereoisomers that are mirror images of each other and hence are non superimpossible are called enantiomorphs. They differ from each other merely by one chiral Centre. Isomers that are non mirror images are diastereoisomers. They may incorporate more than one chiral Centre.

    While geometrical and diastereoisomers are chemically different molecules, enantiomorphs have indistinguishable chemical and physical belongingss, except for the manner in which they rotate plane polarized visible radiation. Enantiomorphs are of great significance in therapeutics as all biological systems represent a chiral environment. Hence drug action every bit good as temperament ( soaking up, distribution, metamorphosis and riddance ) may differ between enantiomorphs.

    DRUGS AS Enantiomorphs

    As discussed above, the pharmacokinetic and pharmacodynamic belongingss may change for each single enantiomorph. In 1992, United States Food and Drug Administration ( US FDA ) published a policy for development of new stereoisomeric drugs. Approximately 50 % of all marketed drugs are found to be racemates. Although many drugs can be safely administered as racemates, some others show better efficaciousness and fewer side effects when administered as a individual enantiomorph. For illustration, cardiac toxicity of the local anesthetic agent, Levobupivacaine is chiefly associated with R-enantiomer.

    Further, some drugs undergo chiral inversion inside the organic structure to the other enantiomorph ( e.g. Ibuprofen: Non-steroidal anti-inflammatory agent ) and some others undergo racemisation after disposal. This is of peculiar concern, particularly if one of the enantiomorphs is toxic. Hence measuring drugs for their stereochemistry is deriving importance.

    Some illustrations of some individual enantiomeric drugs which have gained importance, compared to their racemate opposite numbers are given below, due to their improved pharmacodynamic- pharmacokinetic profiles:


    The usage of levo – dihydroxyphenylalanine alternatively of racemic dihydroxyphenylalanine has resulted in decrease in dosage and inauspicious effects ( sickness, purging, anorexia, agranulocytosis )


    This proton-pump inhibitor, which is the S-enantiomer of Omeprazle has shown lower first base on balls consequence and higher plasma half life compared to the R-enantiomer, therefore keeping the intra-gastric pH above 4 for a longer continuance. S-enantiomer besides showed decrease in variableness of response between patients.


    It is a Quinolone antibiotic. As there are little differences in temperament between enantiomorphs of this drug, a individual S-enantiomer is preferred.


    S-enantiomer has shown increased hyper reactivity of air passage, sensitiveness to allergens and some lessening in bronchodilator authority. While R-Salbutamol gives significantly higher bronchodilator consequence and lesser side effects.


    This drug is found to be tenfold more powerful than its S-enantiomer when used to handle attending shortage hyperactivity. The presystemic metamorphosis and temperament of the drug is enantioselective in nature. Further, the R-enantiomer shows rapid oncoming of action and decreased inauspicious effects


    This undertaking aims to find the rates of glucuronidation of enantiomeric braces, of a broad scope of drugs, to place differences in metamorphosis between enantiomorphs of a drug and besides to happen out whether enantioselectivity is related to a peculiar household of UDP-glucuronosyl transferase ( UGT ) enzyme. Experiment may be done by in-vitro incubations of human recombinant UGTs or human liver microsomes with the selected substrates, followed by analysis utilizing liquid chromatography ( HPLC ) equipped with a mass spectrometer for sensing.

    Laboratory analysis of enantiomorphs is normally done utilizing any one of the undermentioned two methods:

    • Chiral Chromatography, which make usage of a chiral column or chiral nomadic stage to divide the enantiomorphs.
    • Derivatisation, of the analyte utilizing a chiral derived function followed by separation of the ensuing diastereoisomers utilizing criterion, achiral chromatographic method.
    • But in the instance of separation of drug conjugates, the analytical procedure is comparatively simple, as the glucuronide conjugates behave merely like derivatised diastereomers and hence may be separated by conventional liquid chromatography.


    Many late phase failures in drug development procedure are due to inability to foretell the pharmacokinetic belongingss of new chemical entities ( NCE ) before obtaining informations from clinical tests. Hence in-vitro attacks like computational ( in-sillico ) modeling of drug metamorphosis is deriving credence in the recent times. Many attacks such as 2D-Quantitative Structure Metabolism Relationship ( 2D- QSMR ) , 3D-Quantitative Structure Metabolism Relationship ( 3D- QSMR ) , Pharmacophore Identification every bit good as Non-linear form acknowledgment techniques are being studied to pattern drug metabolizing enzymes. Although prognostic theoretical accounts for metamorphosis of drugs by the Phase 1 metabolizing enzyme, Cytochrome P450 are widely accepted, development of effectual theoretical accounts for UDP-glucuronosyl transferases ( UGTs ) catalyzed Phase 2 metamorphosis has received much less attending.

    Versatility of these group of metabolic enzymes, in footings of wide but overlapping substrate specificity, drug-drug interactions, familial polymorphisms every bit good as presence of a big figure of isoforms are some of the challenges confronting the development of predictable theoretical accounts for UGTs. Furthermore, apart from a few catalytically relevant amino acids, the full X-ray crystal construction of UGT enzyme is non yet elucidated.

    Depending on the parametric quantities being modelled ( e.g. Km, Vmax etc. ) a figure of physico-chemical and molecular forms, such as molecular size, form, lipophilicity, H bonding etc. , are required to pattern molecular acknowledgment of substrates and contact action by UGTs. Apart from this, survey of electronic nature of the nucleophile and pKa is besides important. Since chirality plays an of import function in finding metabolic behavior of drugs, design tools may be developed that reference the issue of chirality. While 2D-descriptors will merely foretell molecular connectivity, 3-D theoretical accounts foretelling the enantiomeric belongingss of enzyme-substrate interactions might significantly better the hereafter of drug development procedure.


    In decision, many biological systems represent a chiral environment. Therefore measuring the enantioselectivity of drug metabolizing enzymes plays a important function in foretelling pharmacokinetic behavior of drugs. The present undertaking aims at placing the enantio-selectivity of drugs in UDP-glucuronosyl transferase ( UGT ) metamorphosis, which is an of import Phase 2 ( junction ) procedure of drug metamorphosis. Furthermore, cognizing the enantiomeric behavior may assist in the development of 3D-Quantitative Structure Metabolism Relationship ( 3D-QSMR ) theoretical accounts for foretelling drug metamorphosis.

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