Each question is worth a total of 100 marks.
Describe how physiological adaptations of the gastrointestinal tract allow this organ to fulfil its primary functions.
Drug X, structure shown below, has a molecular weight of 257, a calculated Log P value of 2.4 and a pKa of 9.5, undergoes hepatic metabolism to yield a variety of Phase I and II metabolites.
Draw the chemical structures of five potential metabolites of drug.
Name the type of metabolic transformation that the drug, or a metabolite of the drug, has undergone for each metabolic route you have indicated.
For each transformation name the enzyme system(s) likely to have mediated the transformation, their subcellular location and cofactor requirements.
Comment on the alteration in the physicochemical properties of the metabolites compared to the drug and explain how the structural modifications involved influence the excretion of drug related material from the body.
Compare and contrast the physical instability of emulsions and suspensions.
Discuss the role of flocculating agents in the design of a suspension formulation.
Following intravenous administration of 200 mg of a drug to a healthy volunteer the plasma concentration versus time curve may be described by the equation:
Ct = 4.17e–0.24t
Where the plasma concentration (Ct) is in units of micrograms per millilitre (μg/mL) and the time (t) post drug administration is in hours.
The drug was subsequently given orally at a dose of 300 mg to the same volunteer yielding an area under the plasma concentration time curve of 23.2 mg L–1 h.
Using the above information, calculate the following pharmacokinetic parameters of the drug:
volume of distribution,
area under the plasma concentration time curve,
Further examination of the properties of the drug indicate that it has a therapeutic range between 2.0 and 8.0 mg/L in plasma concentration. Calculate the maximum, minimum and average plasma concentrations of the drug if the oral dose was repeated at 6 hourly intervals. Do the maximum and minimum concentrations fall within the therapeutic range?
It is estimated that more than 40% for new chemical entities coming out of the current drug discovery process have poor biopharmaceutical properties such as low aqueous solubility and/or permeability. This poses a significant challenge for the oral absorption of new drug compounds and for the development of orally bioavailable dosage forms. Discuss the advantages of formulating drugs in development as soft gelatin capsules compared with a tablet formulation in relation to their manufacture, bioavailability and applicability to BCS class II and class IV compounds.
Drugs that target organisms from the kingdom ‘mycota’ may often be ineffective against species of mycota that are in the group ‘pseudo-fungi’. Explain how the biochemistry of fungi and pseudo-fungi differs such that certain drugs, such as the azoles, triazoles or enchinocandins, which are very effective in treating various true fungal infections are ineffective in treating pseudo-fungal infections, whilst the polyene class of drug, such as Amp-B, are able to treat both types of infection.
The following is the physical properties of two drugs. Discuss the challenges of producing 250mg tablets of the two drugs using direct compression. Discuss what excipients (give at least three examples) and production measures could be used to overcome the challenges.
Drug A: 10mg dose, poor flow properties and poor compaction properties
Drug B: 50mg dose, poorly water soluble, micronized particles, reasonably good compaction properties