Drug Zafirlukast/bioavailability - Essay Example

An Analysis of how Drug Degradation, Diffusion, Partitioning and Permeability Influence Bioavailability of Drugs in Vivo This paper discusses how drug degradation, diffusion, partitioning (transport) and permeability influence the bioavailability of drugs in vivo and it will focus particularly on two derivatives (derivative 1 and derivative 2) in comparison to the parent drug Zafirlukast. Bioavailability measures the amount of the drug that has entered the patient’s systemic circulation (Martin, Warwick, Dane, Brindley & Short, 2003).

Drug absorption depends on degradation, diffusion, transport and permeability factors of the drug which in turn influence its bioavailability. Permeability measures the ability of the drug to cross the plasma membrane as a function of distance over time (Verbeeck, Blackburn & Lowen, 2003). Drug absorption is in turn determined by molecular properties of the drug. The study focused on the analysis of Total polar surface area (TPSA), molecular weight and Log P to investigate possible correlation between these properties and bioavailability.

TPSA refers to the sum of all polar atoms on a drug molecule (Martin et al., 2003). Log P is a measure of the hydrophobicity of a molecule. Zafirlukast is an oral leukotrine (LTRA) antagonist, used for the maintenance treatment of asthma (Surhone, Timpledon and Marseken, 2010).Key words: Zafirlukast, Bioavailability, Permeability, Log P, Molecular weight and Total polar surface area (TPSA).An Analysis of how Drug Degradation, Diffusion, Partitioning and Permeability Affects Bioavailability of Drugs in VivoDrug absorption and bioavailability are vital drug factors that determine how much of the dosage is able to reach the patient’s systemic circulation.

In an attempt to investigate how these factors influence bioavailability, the study focused on the three molecular properties that are TPSA, Log P and molecular weight. Drug molecules with a higher TPSA have the capability of forming the H- bond with water leading to higher solubility and hydrophilicity. However, hydrophilicity is a barrier against the process of drug molecule crossing the intestinal lining during absorption as it increases the permeability of the drug molecule. In contrast, to TPSA, Log P is a measure of hydrophobicity (Martin et al., 2003). Hydrophobicity enhances permeability by increasing the rate of the drug molecule crossing the intestinal lining resulting in a higher bioavailability.

In addition, high molecular weight of a drug molecule slows the rate of drug permeability leading to low bioavailability.From case 1 of the case study, we used GASTRO PLUS and determined that parent Zafirlukast had a calculated permeability of 0.453 times 10 -4 cm/s. A high molecular weight would show a decrease in bioavailability as deduced from experimental values. However, this does not correlate with the parent drug and the two derivatives. Despite having higher molecular weights as at 606.

701 times g/mol for derivative 1 and 729.255g/mol for derivative 2, than Zafirkulast at 575.637 g/mol, the derivatives 1 and 2 had predicted permeability values of 2.289 times 10-4 and 0.976 times 10 -4 respectively. On the other hand, it was expected that a greater TPSA would result to a lower permeability and consequently a decrease in bioavailability as a concurrent decrease in hydrophobicity. The use of mol inspiration revealed that Zafirlukast, derivative 1 and derivative 2 had TPSA values of 115.74, 172.985 and 158.

834 respectively. While the increased TPSA values showed a decrease in bioavailability as predicted by the derived trend line of experimental data points, the values can be considered a suspect because they gave negative values of -9.36 times 10-4 cm/s for derivative 1 and -7.34 times 10-4cm/s for derivative 2 which are impossible. The last property which is Log P, a function of hydrophobicity, should increase with permeability. Accordingly, the trend line predicted that derivative 1 would have 5.

04 times 10-4cm/s while derivative 2 would have 5.47 10-4cm/s. However, Zafirlukast has a Log of 5.686 compared to 3.701 of derivative 1 and to 6.65 of derivative 2.In the previous study, Zafirkulast had a bioavailability of 80%. According to the derived equation for molecular weight, the increased values for the molecular weight were supposed to show a decrease in bioavailability. This proves to be the case because derivative 1 showed 47% while derivative 2 had 37%, which are lower, than the experimental value for Zafirlukast.

In relation to permeability, the TPSA was found to have a negative trend line and the predicted values were 44% for derivative 1 and 48% for derivative 2, which gives the expected values lower than the parent drug. Lastly, using the Log P values, derivative 1 and derivative 2 were expected to have bioavailability of 59% and 61% respectively. This does not compare to the actual Zafirkulast in which it was expected that derivative 1 to be lower compared to the parent drug while derivative 2 to be higher.

In general, the values for predicted permeability for the Zafirkulast derivatives were slightly higher than the GASTRO PLUS values. These values were based on TPSA, Log P and molecular weight. To get the predicted permeability values for our derivatives, we averaged molecular weight and Log P but left out TPSA values which had given negative numbers that seemed suspect. The permeability values for the derivatives could have been higher than the GASTRO PLUS values due to the omission of the TSPA values.

On the other hand, when we examine the GASTRO PLUS values for bioavailability, Zafirkulast stands at 72.9% absorption which was very close to the predicted literature value of 80%. However, the Zafirkulast derivatives’ bioavailability was not close to the predicted values. Derivative 1 had a much higher value than expected while derivative 2 had a much lower value than predicted. Bioavailability took into account all the three parameters. Thus, it’s important to note that many factors come into play when determining bioavailability.

It’s possible that the GASTRO PLUS value for derivative 2 was lower than expected because GASTRO PLUS underestimated the permeability of derivative 2 which might have helped to deflate the value, while derivative 1 was higher than predicted because GASTRO PLUS may have overestimated the drugs hydrophilic factors and assumed overall better bioavailability. Bioavailability is a complex phenomenon making it difficult to determine which factor has the most importance in vivo.When comparing derivative 1 to Zafirkulast, derivative 1 has a higher dissolution rate but a smaller permeability due to the presence of the phenol, aniline and alcohol groups.

These functional groups increase the hydrophilicity of derivative 1 making it easier to dissolve. The additional groups will also make it harder for derivative 1 to cross the hydrophobic lipid membrane. A problem with the high dissolution rate is that it might cause derivative 1 to start dissolving prior to reaching to the intestines. Acidic PH in the stomach increases rates of degradation making dissolution problematic. As a corrective measure, derivative 2 will have a 1% reduction in the disintergrant content (croscarmellose, sodium and hypromellose) and 1% increase in the amount of binder (lactose and microcrystalline cellulose).

This will make total of 2 mg binder and 0.4 mg disintergrant. Additional binder content will make the drug more cohesive. On the other hand, additional disintergrant will slowdown the drug’s rapid breakdown.ReferencesMartin, P., Warwick, M., Dane, A., Brindley, C., and Short, T. (2003). Absolute oral bioavailability of rovustatin in healthy adult male volunteers: Clinical therapeutics 25(10).Retrieved November 16, 2011 from< http://linkinghub.elsevier.com/retrieve. Verbeeck, R.K., Blackburn, J.L., and Lowen, G.R. (1983).

Clinical pharmacokinetics of non steroidal anti inflammatory drugs. Clinical pharmacokinetics 8(1983). Retrieved November 11, 2011 from. Http://www.ncbi.nlm.nih.gov/pubmed/6352138>. Surhone, M., Timpledon, M. and Marseken, S. (2010).Zafirlukast. Saarbrucken, Germany: VDM Verlag Dr. Mueller AG and Co Kg.