Raltegravir belongs to the class of integrase inhibitors. It is the first integrase inhibitor to be registered.Â The drug was approved by the U.S. Food and Drug administration (FDA) in October 2007. Integrase inhibitors work by blocking the integrase enzyme which catalyses the insertion of the viral DNA into the host cell's DNA. This process stops the multiplication of viral genetic information and therefore no new viral cells are produced. This prevents other cells from being infected.
Raltegravir was previously known as MK-0518. The brand name for Raltegravir is isentress. This drug must be used with other retroviral drugs to treat HIV. The drug is also used to treat HIV infections which are resistant to multiple antiretrovirals such as non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (Merck & Co, 2010).
To understand the mechanism of the drug we need to first understand how the enzyme works. Human immunodeficiency viruses belong to retroviruses. Retroviruses are those which have RNA as their genetic material. The virus attacks CD4+ T cells once inside the human body, and injects the RNA and their cellular components into the host cell. The viral RNA is converted into viral DNA by a viral enzyme called reverse transcriptase. The viral DNA then enters the nucleus of the infected cell where it uses the host cell's DNA to copy the viral DNA.
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The next step is the integration. Integrase is the viral enzyme which catalyses the integration of viral genetic material into the infected cell's DNA. Integrase catalyses the 3' termini by removing dinucleotides from 3' ends on both sides of viral DNA (Savarino, 2007). This leaves OH groups exposed on both termini resulting in the formation of a pre-integration complex, which then travels from the cytoplasm to the nucleus. The strand transfer step takes place in the nucleus and the proviral DNA is formed upon the insertion of the integration complex into the host cell's DNA. The gaps are then filled by cellular repair proteins.
As raltegravir is an integrase inhibitor, it prevents the insertion of the HIV DNA into the host cell's DNA by blocking the integrase enzyme. The HIV genome itself can not produce the new virus particles. Thus the viral infection does not spread out in the body (eMC, 2010).
Structure, formula, functional groups
The chemical name for raltegravir is N-[(4-Fluorophenyl) methyl]-1, 6-dihydro-5-hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1, 3, 4-oxadiazol-2-yl) carbonyl] amino] ethyl]-6-oxo-4-pyrimidinecarboxamide monopotassium salt (Sathish et al. 2008). The empirical formula of the drug is C20H20FKN6O5,Â and the molecular weight is 482.51 Daltons (Sathish et al. 2008).
The functional groups of the drug include a halogenated aromatic ring, aliphatic hydrocarbons (methyl groups), imine groups, ether, and amide groups.
Halogenated aromatic ring
Stereochemistry and conformation
Raltegravir is an achiral drug as it does not have any chiral centre. The drug therefore does not have any enantiomers. There is also no stereoisomer for the drug as there is no chiral centre as the number of stereoisomers is determined from the number of chiral centres. If there is n number of chrial centres the number of stereoisomers would be 2n.
Staggered conformation would be favourable as there would be less steric hindrance between large groups. The adapted conformation would be complementary to the target where the drug acts upon. There are three rings in the structure taking up most of the space. The atoms arrange in such a way that they are as far as possible from each other. The staggered conformation will have the lowest energy and would be the most stable. Eclipsed conformation is not stable as it has the highest energy. Isentress has 7 freely rotatable bonds. The bonds can rotate resulting in 7 different conformations (Scifinder Scholar, CAS).
The drug has two hetrocycles - cyclic compunds which have one or more heteroatoms such as nitrogern, onygen and sulphur. The two heterocycles are the substituted oxadiazole ring and the substituted pyrimidine ring. Pyrimidine ring is also found in the humans' genetic material, DNA. The nucleic acids of human DNA consist of a deoxyribose, a phosphate group and a nitrogenous base. The bases cytosine and thymine contain substituted pyrimidine rings. The uracil base of RNA also has a substituted pyrimidine ring. The bases cytosine and thymine are complementary to guanine and adenine as they can from hydrogen bonds with them. Similarly raltegravir also can from hydrogen bonds with the enzyme integrase due to the presence of the substituted pyrimidine ring. Raltegravir can also be referred as an alkaloid as there is more than nitrogen in the structure.
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Substituted pyrimidine ring
Substituted oxadiazole ring
Synthesis, formulations and packaging
Raltegravir is formulated as potassium salt. Its physical description is white to off-white powder. The drug is produced as tablets for oral administration. The tablets are pink oval shaped (Merck & Co, 2010). The tablets have coating on them for effective absorption inside the body. The extent of absorption and release of the drug in the blood depends on its hydrophobicity and hydrophilicity. If the drug has a hydrophilic coating it will be absorbed more quickly in the GIT and released rapidly in the blood. The absorption and release would slow down if the drug has a hydrophobic coating. The excipients in the coating are polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide (eMC, 2010).
The film-coated tablets contain 434.4mg of raltegravir potassium as a slat which is equivalent to 400mg tablets. The inactive ingredients in raltegravir are microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate (Sathish et al. 2008).
The tablets are packed in High density polyethylene (HDPE) bottles with a child-resistant polypropylene closure (eMC, 2010). The packaging in plastic bottles indicates that the drug does not undergo free radical oxidation as the chemicals undergoing free radical oxidation have to be packaged in brown bottles or foil packaging.
The drug is available in two packs; a bottle of 60 tablets and multiple-pack of 180 tablets comprising of 3 packs of 60 tablets. There are not any special storage conditions for the drug. It is stored at normal room temperature. The shelf life of the drug is 30 months. The long shelf life and packaging in normal plastic bottles represents that raltegravir is a quite stable drug (Rx list, 2010).
Drug stability: Potential sites of chemical instability and metabolism
The presence of ester groups makes a drug instable towards hydrolysis. Raltegravir does not have any ester group so it can not undergo hydrolysis. Some chemicals can donate atoms to get stabilised by resonance. Raltegravir has more than one resonance form. The more resonance forms a molecule has the stable the molecule is. The lone pair of electrons on the oxygen atom can move in any direction.
The following resonance diagrams show a few possibilities of the transfer of electrons and how different atoms stabilise by resonance.
The lone pair of the electrons can move to the carbon of the amide group on either side as the red arrow shows in the diagram above.
Christopher A. Lipinski formulated the rule of five in 1997 regarding the bioavailability of orally active drugs. The rule gives an indication of a drug's absorption and permeation in the biological systems but the pharmacological activity can not be predicted from the rule (Caltech library services). Lipinski stated (Lipinski, 1996) in his rule that a compound should have five or fewer H-bond donors, ten or fewer H-bond acceptors, molecular weight less than or equal to 500, and Log P value less than or equal to 5. Compounds that are classed as substrates for biological transporters are exceptions to the rule.
Raltegravir has 3 H-bond donors and 11 H-bond acceptors (Scifinder Scholar, CAS). Nitrogen and oxygen are the atoms which can accept and donate protons forming H-bonds. The hydrogen bonds stabilise the compound and there would be strong interactions between the drug and its target, integrase. Raltegravir obeys the lipinskis rule up to some extent as it has less than 5 H-bond donors and just one more H-bond acceptor than the rule states.
Raltegravir follows the lipinskis rule in the way that its molecular weight is 482.51 Da which is less than 500. Log P is the log of partition coefficient. Earll (Earll, 1999) defines the partition coefficient as "the ratio of concentration of compound in aqueous phase to the concentration in an immiscible solvent, as the neutral molecule". The range of Log P value given at Chemical Abstract Services (Scifinder Scholar, CAS) is from -1.7 to +0.3 (-0.676Â±1.000). The log P value agrees with the lipinskis rule as it is less than 5. The partition coefficient can be calculated by taking antilog of log P. We get 0.21 by taking antilog of -0.676. It means that only 21% of raltegravir will cross the lipophilic phospholipid bilayer, and 79% of the drug will stay in the blood plasma due to the presence of a number of hydrophilic groups. Amines, amides, ether and the hydroxyl group are the polar and hydrophilic groups in raltegravir whereas the aliphatic and aromatic hydrocarbons are the non-polar hydrophobic fragments. The hydrophilic groups can form strong hydrogen bonds. This is also the reason that raltegravir is soluble in water and slightly soluble in organic solvents like methanol and propanol (Rx list, 2010).
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The pKa of the conjugate acid is 0.42 which means that raltegravir is a very weak base (Scifinder Scholar, CAS). It will not readily accept protons because the lone pairs of electrons on both the nitrogen atoms of oxadiazole ring are not available as both the nitrogen atoms are sp2 hybridised.
Raltegravir has a pKa value of 4.50 which shows that raltegravir is acidic. The drug stays in the acidic from as it is stabilised by resonance in this state. The pKa value can be used to determine the ionisation state at different pH values. The Henderson-Hasselbach given below can used to determine the % of ionised drug at a certain pH.
% of ionisation = 100 / [ 1 + antilog (pKa - pH) ]
At pH 2, % of ionisation = 100 / [ 1 + antilog (4.5 - 2) ] â‰ˆ 0%
The drug will be in its acidic form at pH 2 of the gastric fluid as the pH is lower than the pKa. The drug will be 100% unionised at pH 2 and it will easily be absorbed in the stomach as it can cross the membrane. At pH 7 the drug will be almost 100% ionised so it will not cross the phopholipid bilayer membrane and will be dissolved in the plasma. Similarly the drug will be 100% ionised at pH 10 and will not cross membranes. The drug will therefore be absorbed in the stomach at pH.
The prescribed dosage is 400mg to be taken twice daily, with or without food. The maximum absorption time inside the body is about 3 hours (Rx list, 2010). No adjustments are required in the dosage form in patients with different age, gender, race, and ethnic origin. The drug can not be prescribed to children less than 16 years of age. The common side effects of the drug include nausea, headache and diarrhoea (BNF). The medicine should not be used during pregnancy as recommended by the manufacturer. No research has been conducted in pregnant woman but the drug is found to be toxic in animals (BNF). The drug can reduce the viral load to undetectable in the plasma and significantly increase the number of CD4 cells (Isentress patient brochure, 2010).