Unit 2 C. Principles of pharmacokineticsObjective 1: Define bioavailability and describe the factors that can modify absorption. Bioavailability is the fraction of the dosage form that reaches the systemic circulation after any route of administration. In this particular study, acetaminophen was administered orally, intravenously, and rectally to healthy men aged 18 to 45 years and the pharmacokinetic parameters were compared for each route. The study assumed IV bioavailability to be 100%. The bioavailability of the oral dose was 89% and 72% for the rectal dose. Drug interactions, intestinal motility, gastric pH, and stomach emptying can all alter absorption. In this study, key exclusion criteria were implemented to attempt to minimize the risk of these factors influencing the results. For example, this study was limited to healthy men who weighed at least 50 kilograms and tested negative for any immune deficiency. Ideally, this would eliminate factors that could alter absorption, such as any disease state. All participants were also non-smokers. Some studies have shown that chronic smoking can increase acid secretion in the stomach. Thus, by eliminating smokers from this study, the risk of gastric pH affecting the results was minimized. Finally, use of medications or supplements within 7 days prior to administration of the first dose of acetaminophen was not permitted. Additionally, during the 3 days of the study, no other medications were allowed to be administered. Together, these factors eliminated the risk of drug interactions affecting acetaminophen pharmacokinetics. Objective 2: Explain the relationship between clearance and half-life. Clearance is the removal of the drug from the body and half-life is how long it takes. ..... middle of paper ......have been diminished. When administered with probenecid, the concentration of unchanged paracetamol was significantly higher than when administered without probenecid. Indeed, probenecid inhibits UDPG-transferase. UDPG transferase is a key enzyme responsible for phase 2 conjugation, so if it is inhibited, less paracetamol will be converted to its metabolite, paracetamol, the glucuronide. This is why the clearance of this metabolite decreases when drugs are taken simultaneously. Renal elimination was decreased for both acetaminophen metabolites because probenecid inhibits the process of active transport in the kidneys that causes secretion of the metabolites into the tubules. Since the metabolism of paracetamol is reduced when taken with probenecid, there is a risk of adverse effects. A greater amount of the active parent form of the drug in the body may lead to potential hepatotoxicity in patients..