Population Pharmacokinetics and Bioavailabilty †MyAssignmenthelp

Question: Discuss about the Population Pharmacokinetics and Bioavailabilty. Answer: Introduction: Pharmacology is a discipline of science that tends to decipher the kind of Management interactions that do exist or occur between various kinds of chemicals and the living systems (Teferra et al, 2004). One of its major subdivisions is pharmacokinetics that mainly deals with the study of what the body does to an ingested drug. It evaluates the drugs adsorption, distribution, metabolism and excretion (Teferra et al, 2004). This presentation seeks to decipher the drug Tacrolimus in the lines of its basic pharmacology including the mechanism(s) of action of the drug, its toxicities, adverse effects, the clinical uses ad dosages and/or formulations available, its chemical structure and/or characteristics and how they relate to its interesting pharmacokinetic characteristics and their clinical implications, its contraindications in special populations, and finally provide a concrete and comprehensive solution to the case study 4. Tacrolimus also often referred to as FK-506 or fujimycin, is the generic name for drug Progaf/ Hecoria/ Protopic/ Advagraf. It is a prescription only drug given to post transplant patients to prevent organ rejection following allogeneic liver, kidney, and/or heart transplants. It achieves this by way of decreasing the action of the individuals immune responses and as such, it is an immunosuppressant. Its mechanism of action, therefore, is by inhibiting the production of interleukin-2 which are molecular components that promotes the development and proliferation of the T lymphocytes by preventing the dephosphorylation of nuclear factor of activated T-cell (NF-AT) that increases the activity of genes coding for IL-2 and related cytokines (Ganong, 2005). This places the drug in the calcineurin inhibitor immunosuppressant drug class. It is also used in the treatment of other T cell-mediated diseases such as eczema, treatment of severe refractory uveitis after bone marrow transplants and in the exacerbations of minimal change disease. It is more potent than other drugs such as cyclosporine used in immunosuppression (Haddad et al, 2006). The available preparations include the oral common twice-daily formulation (Progaf), once daily formulation (Advagraf and Envarsus), and the topical formulation or ointment (Protopic). It is a macrolide lactone with the chemical structure: C44 H69 NO12 (Dirk, 2003). Because of its acidic properties, the drug is absorbed in acid environments of the stomach and dissociates in the basic environment of the intestine where some its metabolism begins. This acidic property makes it highly bound to proteins in the blood and to the erythrocytes explaining its high protein binding rate. Tacrolimus is given orally with a bioavailability of 24%. Its absorption rate decreases with intake of food rich in fat. Its take one to three hours to attain its highest blood plasma concentrations and the protein binding rate of the drug is 98.8% and it binds to albumin and alpha1-acid glycoprotein. The drug is metabolized in the liver by the cytochrome P450 metabolic enzymes: CYP3A4 and CYP3A5, and in the intestinal wall. It is mostly excreted through the feces. It has a biological half-life of 12 hours in transplant patients but this is higher in healthy individuals with biological half-life of up to 43 hours. Since the drug is absorbed in the gut, it undergoes first pass metabolism that reduces its bioavailability but the high protein binding rate limits the dose as it increases its half-life. The clearance of Tacrolimus is 2mg per hours and its volume of distribution is 98 (Marie et al, 2007). Its drug interaction occurs with the following drugs and as such should not be taken together with these drugs: Management asenapine, cisapride, and citalopram, a potassium-sparing diuretic such as spironolactone, mifepristone, streptogramin, ziprasidone, and cyclosporine. It is contraindicated in patients with castor oil allergies, any allergic reactions to any other component of the drug, in pregnant and breastfeeding individuals, in individuals with chronic infections, diabetes, high blood potassium levels, hypertension, with weakened immunity, anemia, heart, kidney, or liver problems, skin cancer, in individuals scheduled to receive live vaccines and in individuals taking other medications to suppress their immune system. The side effects of the drug differ depending on the route of administration. For oral and intravenous administration, the side effects include various types of infection, heart damage, high blood pressure, disturbed vision, hepatic and renal problems(Tacrolimus nephrotoxicity), hyperkalemia, low blood concentrations of magnesium (hypomagnesaemia), high blood glucose levels, diabetes mellitus, itching, lung damage, and neuropsychiatric problems e.g. loss of appetite, insomnia, confusion, depression, and vivid nightmares. It increases the severity of pre-existing fungal and/or infectious conditions (Dimitrios and Pramateftakis, 2013). It increases the risk of malignancy and various types of cancer. The topical Tacrolimus ointment applied over wide areas cause burning sensations on the initial application and an increased sensitivity to UV light and heat on the affected areas. After oral administration, drug plasma concentration can be obtained by the help of the above equation where C is the plasma concentration, F is the bioavailability, D is the dose, ka is the absorption rate constant, ke is the elimination rate constant, Vd is the volume of distribution and t is time. References Dirk K. (2003). Long-Term Clinical Pharmacokinetic Study of Management Tacrolimus and Mycophenolic Acid and Metabolites in De Novo Renal Allograft Recipients. Leuven University Press, 6 Dimitrios R., Pramateftakis M. G. (2013).Tacrolimus: Effectiveness, Safety and Drug Interaction. Nova Science Publishers, Incorporated. Ganong W. F. (2005). Review of Medical Physiology. 22nd Ed. Lange Medical Books. 530 Haddad, E. M., McAlister v. C., Renouf E., Malthaner R., Kjaer M. S., Gluud L. L. (2006). Cyclosporine versus Tacrolimus for Liver Transplanted Patients. McAlister V, ed. Cochrane Database of Systematic Reviews. 4(CD005161): CD005161. Marie A., Benoit B., Robert F., Philippe L., and Urien S. (2007). Population Pharmacokinetics and Bioavailabilty of Tacrolimus in Kidney Transplant Patients Management. Soraya D. and Kiren G. (2006). Basic Pharmacology. 2nd Edition. [PDF]. Retrieved from www.dandybooksellers.com/acatalog/9780853695714.pdf Accessed on 9th May 2017. Teferra, A., Srinivasa, A. R., Mengistu, S. W., Eshetu, L., Musei, A, and Dawit. (2004). Lecture Notes for Health Science Students: Pharmacology. 1-5