Zidovudine is an antiretroviral drug which is a ‘nucleoside contrary RNA polymerase inhibitor ‘ ; it is used as intervention with other antiretroviral drugs against the Human Immunodeficiency Virus. Additionally, Retrovir can be utilised as a agency of cut downing the hazard of transportation of HIV from a pregnant adult female to her kid. Furthermore, Retrovir is used in ‘post exposure prophylaxis ‘ in order to take down the opportunity of being infected with HIV in people who have been ‘exposed ‘ to the virus. ( AHFS Drug Information, n.d. ) .
Name Of Drug, Structure, Formula and Functional Groups
Zidovudine is besides known as ‘azidothymidine ‘ and, in short, ‘AZT ‘ ( Joint Formulary Committee, 2010 ) . The molecular expression of the compound is C10H13N5O4 ( The Merck Index, n.d. ) and Retrovir has a molecular weight of 267.25, as calculated utilizing the ISIS ChemDraw bundle ( Cambridge Soft, n.d. ) . Analyzing the compound shows that Retrovir is made up of a T group bonded to a 2′,3’-dideoxyribose group with an affiliated azide group. Therefore the systematic name of Retrovir is 3?-azido-2 ‘ , 3?-dideoxythymidine ( The Merck Index, n.d. ) , as the O of the hydroxyl group on the 3 ‘ C of the ribose ring has been removed, giving 3’-deoxyribose, and has been replaced with an azide group and the O on the 2 ‘ C has besides been removed.
The azide group on the ribose ring is the ground why Retrovir acts as a ‘nucleoside contrary RNA polymerase inhibitor ‘ ( AHFS Drug Information, n.d. ) . In order for Retrovir to transport out its function, it must be ‘phosphorylated ‘ by an enzyme called ‘thymidine kinase ‘ ; this is due to the fact that rearward RNA polymerase includes the ‘triphosphates ‘ produced into the HIV DNA concatenation being formed during HIV reproduction. Consequently, after the triphosphate has been included, ‘5 ‘ , 3’-phosphodiester bonding ‘ in the Deoxyribonucleic acid concatenation is non possible, because of azide group in the triphosphate, and hence DNA formation can non go on ( Foye et al, 2008 ) .
Figure 1. The planar and three dimensional constructions of Retrovir drawn in ISIS ChemDraw ( Cambridge Soft, n.d. ) utilizing the British Pharmacopoeia as a mention ( British Pharmacopoeia, 2010 ) .
Formulations and Boxing
The generic signifier of Retrovir is available as ‘hard capsules ‘ ( Electronic Medicines Compendium, n.d. ) in two strengths of 100mg and 250mg ( Joint Formulary Committee, 2010 ) . Both strengths are packaged in ‘foil blister battalions ‘ and fictile bottles and necessitate to be kept in these ; they have an expiry day of the month of 2 old ages from the day of the month of industry ( Electronic Medicines Compendium, n.d. ) .
Zidovudine is besides available under the trade name name of ‘Retrovir® ‘ in the signifier of capsules, unwritten solution and injection solution ( Joint Formulary Committee, 2010 ) . All of the ‘Retrovir® ‘ preparations need to be kept below 30 grades and in their original outer boxes ( Electronic Medicines Compendium, n.d. ) .
The capsules are ‘hard capsules ‘ ( Electronic Medicines Compendium, n.d. ) in strengths of 100mg and 250mg ( Joint Formulary Committee, 2010 ) ; they have an expiry day of the month of five old ages from the day of the month of industry and are packaged in a ‘blister battalion ‘ or a bottle ( Electronic Medicines Compendium, n.d. ) .
The unwritten solution consists of a 50mg in 5ml dosage ( Joint Formulary Committee, 2010 ) and is packaged in an ‘amber bottle ‘ made of glass. The unwritten solution has an expiry day of the month of two old ages from the day of the month of industry but should be disposed of after the bottle has been opened for ‘one month ‘ ( Electronic Medicines Compendium, n.d. ) .
The injection solution is available in the dosage of 10mg per 1ml and is used for ‘intravenous extract ‘ ( Joint Formulary Committee, 2010 ) . It is packaged in a ‘glass phial ‘ which is brownish-yellow or clear in coloring material. The solution has an expiry day of the month of three old ages after the day of the month of industry nevertheless, one time opened, it must be used immediately and any staying solution disposed of ( Electronic Medicines Compendium, n.d. ) .
Harmonizing to Martindale: The Complete Drug Reference ( n.d. ) , all the preparations of Retrovir demand to be shielded from beginnings of visible radiation and demand to be kept in ‘air tight containers ‘ .
Stereochemistry and Conformation
As highlighted in the diagram drawn utilizing ISIS ChemDraw ( Cambridge Soft, n.d. ) , Retrovir has a sum of three chiral Centres and hence Retrovir has eight possible stereoisomers. The 1 ‘ C of the ribose ring is of the R constellation whereas the 3 ‘ and 4 ‘ Cs are of the S constellation ( Novak et al, 2003 ) . Zidovudine has a specific optical rotary motion value of +99 & A ; deg ; in H2O ( Merck, n.d. ) and therefore rotates the plane of polarized light clockwise ; accordingly Retrovir is optically active ( Freeman, 2010 ) .
Zidovudine was made by Jerome Horwitz in 1964 ( Weeks et al, 2010 ) . It can be formed from thymidine, nevertheless, this is a dearly-won method and therefore a more cost effectual technique is used to do Retrovir on a big graduated table by utilizing D-Mannitol as the get downing compound ( Saunders, 2000 ) . The procedure has been drawn below utilizing ISIS
ChemDraw ( Cambridge Soft, n.d. ) with mention to Exceed Drugs ( 2000 ) .
In the first phase, a derivative of D-glyceraldehyde is formed from D-mannitol utilizing propanone and a beginning of protons and refluxing. Lead ( IV ) ethanoate is so added. In the 2nd phase a ‘Wittig reaction ‘ is carried out and ‘PH3P=CHCO2Et ‘ and methyl alcohols are added. In the 3rd measure hydrochloric acid is added, bring forthing a lactone. In the 4th phase the lactone is ‘protected ‘ and the azide group is added on through a ‘Michael add-on ‘ reaction. The reagents used to protect the lactone are ‘t-Bu ( Me ) 2SiCl ‘ , imidazole and dimethylformamide. The reagents for the ‘Michael add-on ‘ reaction are lithium azide, tetrahydrofuran, acetic acid and H2O. In the 5th phase the lactone is reduced to a lactol at minus 78 grades utilizing Diisobutylaluminium hydride and methylene chloride. The hydroxyl group is ‘activated ‘ to organize a ‘sugar intermediate ‘ utilizing acetic anhydride and pyridine. In the 6th measure, ‘Vorbruggen conditions ‘ are adopted and a ‘condensation reaction ‘ is performed with the ‘sugar intermediate ‘ and ‘silylated T ‘ which produces ‘alpha and beta anomers ‘ . The reagents are di-trimethylsilyl-thymine, trimethylsilyl trifluoromethanesulfonate and ‘EDC ‘ . In the 7th measure, the ‘silyl protecting group ‘ is taken away and the ‘anomers ‘ are uncombined to obtain Retrovir. The reagents used in this measure are ‘n-Bu4N+F- ‘ and tetrahydrofuran ( Saunders, 2000 ) .
Drug stableness: Potential sites of chemical instability and metamorphosis
Zidovudine decomposes greatly in the presence of light because of the azide group and the merchandise formed from the dislocation is thymine. This is because two N atoms are removed from the azide group, organizing nitrene. An ‘insertion reaction ‘ takes topographic point and aziridine is made. Water, as a nucleophile, onslaughts aziridine. The amide anion formed causes the T group to be ‘nucleophilically displaced ‘ and therefore T is produced as the debasement merchandise ( Dunge et al, 2004 ) . Therefore as Retrovir is largely affected by visible radiation it is advised that the assorted preparations of Retrovir are kept off from light beginnings ( British Pharmacopoeia, 2010 ) .
Zidovudine has a ‘bioavailability ‘ of 63 % . This is due to the fact that Retrovir undergoes ‘glucuronidation ‘ , giving ‘zidovudine glucuronide ‘ which is more H2O soluble than Retrovir due to a sugar group being added, and is ‘renally excreted ‘ ( Burton et al, 2006 ) . ‘UDP-glucuronyl transferease ‘ is the enzyme which catalyses the reaction ( Veal et al, 1995 ) .
Zidovudine can besides be converted to 3′-amino-3′-deoxythymidine due to the azide group being reduced ( Veal et al, 1995 ) ; 3′-amino-3′-deoxythymidine can impact the action of Retrovir against HIV and is perchance toxic ( Burton et al, 2006 ) .
Lipinski ‘s Rules For Orally Active Drugs
Harmonizing to Clarke ‘s Analysis Of Drugs And Poisons ( n.d. ) the Log P value of Zidovudine is 0.05 and the molecular weight is 267.25 as calculated on ISIS ChemDraw ( Cambridge Soft, n.d. ) . Zidovudine has a sum of two H bond giver sites and a sum of nine H bond acceptor sites ( Lipinski et al, 1997 ) . As a consequence, Retrovir follows ‘Lipinski ‘s Rules of Five ‘ as it has a molecular weight of less than 500, a Log P value of less than 5, there are less than five H bond giver sites and there are less than ten hydrogen bond acceptor sites ( Lipinski et al, 1997 ) .
As the Log P value of Retrovir is 0.05 ( Clarke ‘s Analysis Of Drugs And Poisons, n.d. ) it can be seen that the drug is somewhat polar. Zidovudine contains aromatic and big aliphatic parts which are hydrophobic ; the polar character arises from the hydroxyl group, an amide part, an quintessence nexus and azide group, which are all hydrophilic parts. Therefore as there is a little instability of more hydrophilic groups to hydrophobic groups, Retrovir is somewhat hydrophilic and somewhat polar and therefore is H2O soluble and has less affinity to traverse the lipid membranes ( Bichenkova, 2010 ) .
pKa and Ionization State At pH 2, 7.4 and 10 and Solubility
Harmonizing to the International Agency for Research on Cancer ( n.d. ) , the pKa value of Zidovudine is 9.68 and hence it is decrepit acidic. Using the equation for the per centum of ionisation, which has been derived from the Henderson-Hasselbalch equation, I am able to cipher the per centum sum of ionisation of Retrovir at assorted pH values.
The equation used consists of: % ionisation of an acerb = 100/ 1 + antilog ( pKa – pH ) ( Freeman, 2010 ) .
At pH2, the equation will read % ionisation = 100/ 1 + antilog ( 9.68 – 2 ) . This gives the value 2.09×10^-6 % . Hence it can be seen that in the tummy merely a really little sum of Retrovir will be ionized and by and large it will be mostly nonionized. The per centum of Retrovir unionized at pH2 is 99.99 % and hence as Retrovir is extremely nonionized at pH 2, it will be absorbed from the tummy. At pH2 2.09×10^-6 % of Retrovir is ionized as the azide group can be protonated ( Chemicalize, n.d. ) .
At pH 7.4 the computation gives a value of 0.52 % . Hence in the blood watercourse Retrovir will be mostly nonionized as the per centum of Retrovir that is unionized in the blood watercourse is 99.8 % . In the blood stream 0.52 % of Zidovudine will be ionized as the azide group can deprotonate ( Chemicalize, n.d. ) . As Retrovir is mostly nonionized at pH 7.4, it can be absorbed from the blood stream into the CD4 cells where it carries out its function as an antiretroviral ( Foye et al, 2008 ) .
At pH 10 a value of 67.63 % is obtained. Therefore in basic conditions, Retrovir is mostly
ionized as the azide group is deprotonated and the amide group of T is deprotonated ( Chemicalize, n.d. ) . The per centum of Retrovir unionized in the blood is 32.37 % .
Zidovudine is absorbed really rapidly in the organic structure ( Burton et al, 2006 ) and this can be seen through the fact that Retrovir is greatly nonionized in the tummy and blood watercourse and hence can rapidly come in the CD4 cells in the blood ( Foye et al, 2008 ) .
As Retrovir has an azide group it is able to halt HIV reproduction ( Foye, 2008 ) . Zidovudine follows ‘Lipinski ‘s Rules ‘ and hence is good absorbed in the organic structure ( Lipinski et al, 1997 ) . As Retrovir has a pKa of 9.68, the drug can be absorbed from the tummy as it will be mostly nonionized in the tummy. This is besides the instance for the drug in the blood stream and therefore Retrovir can be taken up rapidly by the cells and transport out its function as an antiretroviral despite being somewhat polar. The bioavailability of zidovdine is limited nevertheless by the fact that some Retrovir is glucuronidated and hence is lost ; some Retrovir is besides affected by the azide group being reduced as the merchandise formed can impact Retrovir ‘s function as an antiretroviral and could be toxic ( Burton et al, 2006 ) . As Retrovir degrades in the presence of visible radiation, the drug is packaged in ‘blister battalions ‘ or ‘plastic bottles ‘ and all preparations of the drug demand to be kept out of visible radiation and in the packaging they came in ( Electronic Medicines Compendium, n.d. ) .