Section 1. Renal Excretion of Drugs and their Metabolites
Determine whether your drug is:
a) Primarily excreted unchanged (as the parent drug) in the urine (renally cleared)
b) Excreted in the urine principally as metabolites (metabolised; hepatically cleared)
Salbutamol is cleared through the urinary system, metabolizing through the inactive 4’-O-sulphate (phenolic sulphate). Within the urine (with a minor extraction method being faeces), both the salbutamol and the metabolite sulphate are excreted. In studies, urinary excretion of salbutamol has resulted in around 64% of a dose being excreted as unchanged salbutamol, with about 12% excreted as the sulphate conjugate (Spina, 2003).
Section 2. Drug Metabolism
For your drug:
a) discuss its metabolism noting the types of reactions, that is either functionalisation or conjugation reactions, and identify the involvement of any CYP, UGT or other drug metabolising enzymes.
Once the phenolic sulphate has been metabolized, it binds itself to the beta-2 receptors that are post-synaptic, thereby causing smooth muscle relaxation in the airway. Mast cells become inactive and cillary action is increased. The mechanism of action involves the R-isomer, a bronchodilator, and the S-isomer, which heightens bronchial reactivity, working as they are bound to the receptor. This leads to bronchodilation and an anti-inflammatory effect, where swelling in the airway lessens (Soriano-Ursua et al., 2010).
b) Identify the main metabolites, and state the percent of the parent compound metabolised to the specific metabolite.
Salbutamol can be administered one of several ways, mainly intravenously and orally (through tablet or inhaler form). Each of these has a slightly different way of metabolizing the drug, and at different rates and concentrations. The primary metabolite in salbutamol is the phenolic sulphate, which comprises either .042% or .021% of the parent drug, depending on whether it is a 1.5mg or .75 mg dose. The drug has a hepatic metabolism, though it is renally excreted. When intravenously administered, the drug directly interacts with the blood plasma protein, the rest moving to the sweat glands to be sweated out, or can be excreted through breast milk (Bonnelykke et al., 2008).
Oral Salbutamol, once entered into the system, is absorbed through the gastrointestinal tract, which then moves via the portal system to the liver. The liver then metabolizes salbutamol to phenolic sulphate metabolite, sending the metabolites to the kidneys and into bile. The metabolites in the kidneys are passed through urine. This bile sends the metabolites back to the GI tract, which passes through fecal matter. When salbutamol is inhaled, it bypasses liver metabolism by working directly on the smooth muscle found in the upper airways (Reszka et al., 2009).
Section 3. Sources of variability in drug metabolism
a) In relation to the metabolism of your drug discuss the influence of host (e.g. disease states) and environmental factors in terms of enzyme induction and/or inhibition on the metabolism of your drug.
Sources of variability in the metabolism of Salbutamol include the method of administration – the drug can be both orally and intravenously administered, both of which have different metabolic rates. Oral tablet administration carries with it a lower metabolism, given the tolerance that the body develops after the previous dosage of 24 hour salbutamol tablets; inhalation metabolizes quickly, as it acts directly on the upper airways, which is the target area (Reszka et al., 2009).
The level of exercise one undergoes while taking salbutamol can also affect the metabolism of this drug. When salbutamol is taken while exercising, glycolysis and lipolysis increases are found, and voluntary muscle strength changes have been observed; this comes from a faster metabolism of the drug. Stimulation of cAMP production as a result of exercise has the effect of mediating the mechanism of action of salbutamol, stemming from the activation of adenyl cyclase enzymes in the body. This leads to a more rapid metabolism of the drug (Soriano-Ursua et al., 2010).
Pregnancy can affect the metabolism of salbutamol as well. When oral salbutamol is introduced into the bloodstream of a pregnant woman, systolic and diastolic pressure decreases and heart rate increases – this is due to the increased metabolic rate experienced during a pregnancy (Hey, 2007).
When salbutamol is taken by someone with hyperthyroidism, metabolism is increased. B-adrenoreceptor numbers become much higher, and as a result the drug works much faster at dilating the patient’s airways. Patients with diabetes must be careful with sabutamol, because increased blood sugar can occur when exposed to salbutamol, due to the metabolic changes that occur. Ketoacidosis can occur when the blood sugar is too high due to the presence of the drug in a diabetic (Soriano-Ursua et al., 2010).
Section 4. Drug-Drug Interactions
For your drug:
a) List all known drug-drug interactions involving the metabolism of your drug.
b) Explain the mechanism of each of the interactions (i.e. Drug A inhibits the metabolism of Drug B by Enzyme X).
Corticosteroids boost the number of B2-andrenergic receptors, which creates a greater response to B2-andregnergic receptor agonists, enhancing the metabolism of salbutamol (Silvanus et al., 2004). Atomoxetine is a selective noradrenaline re-uptake inhibitor that, when combined with salbutamol, increases its toxicity. Salbutamol increases the binding of digoxin to skeletal muscle through mediation of the beta 2 andrenoreceptor (Weiss, 2007).
c) Note the clinical consequences of each of the interactions (e.g. increases the plasma concentration of Drug B leading to an enhanced pharmacological effect and toxicity).
Hypokalaemia can be exacerbated by diuretics, xanthines and corticosteroids. Sympathomimetics, MAOIs, and TCAs can have negative cardiovascular effects. When combined with atomoxetine, blood pressure and heart rate can increase substantially. Digoxin serum levels can be reduced by combination with salbutamol. (Jin et al., 2005).
Bonnelykke, K., Jespersen, J., & Bisgaard, H., 2008, Early bioavailability of inhaled salbutamol reflects lung dose in children. British Journal of Clinical Pharmacology, 66(4), 562-563.
Hey, E., 2007, Neonatal formulary 5 drug use in pregnancy and the first year of life (5th ed.). USA: Blackwell Pub,
Jin, O., Jing, L., Baeyans, W., & Delanghe, J. R., 2005, A simple method for the study of salbutamol pharmacokinetics by ion chromatography with direct conductivity detection. Talanta, 65(1), 1-6.
Silvanus, M. T., Groeben, H., Peters, J., 2004, Corticosteroids and Inhaled Salbutamol in Patients with Reversible Airway Obstruction Markedly Decrease the Incidence of Bronchospasm after Tracheal Intubation. Anesthesiology 100(5): 1052-1057.
Spina, D., 2003, Drugs for the treatment of respiratory diseases. New York: Cambridge University Press.
Reszka, K. J., McGraw, D. W., & Britigan, B. E., 2009, Peroxidative Metabolism of β2-
Agonists Salbutamol and Fenoterol and Their Analogues. Chemical Research of Toxicology, 22(6), 1137-1150.
Soriano-Ursua, M. A., Correa-Basurto, J.C., Romero-Huerta, J.R., et al., 2010,
Pharmacokinetic parameters and a theoretical study about metabolism of BR-AEA (a salbutamol derivative) in rabbit. Journal of Enzyme Inhibition and Medicinal Chemistry, 25(3), 340-346.
Weiss, M., 2007, Mechanistic modeling of digoxin distribution kinetics incorporating slow tissue binding. European Journal of Pharmaceutical Sciences, 30(3-4): 256-263.
Zhang C., Zhang R., Na N., Delanghe J.R., & Ouyang, J., 2011, Direct monitoring changes of
salbutamol concentration in serum by chemiluminescent imaging. Journal of Chromatography, 879(22), 2089-94.