Unit 2 C. Principles of Pharmacokinetics Objective 1: Define bioavailability and describe factors that may alter 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 that IV bioavailability was 100%. The bioavailability of the oral dose was 89% and 72% for the rectal dose. Drug interactions, intestinal motility, gastric pH, and stomach emptying may alter absorption. Key exclusion criteria were implemented in this study to try to minimize the risk of these factors influencing the results. For example, this study was limited to healthy males who weighed at least 50 kilograms and tested negative for any immunodeficiencies. This would ideally eliminate factors that can 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, so by eliminating smokers from this study, the possibility of gastric pH influencing the results was minimized. Finally, the use of medications or supplements was not permitted within 7 days prior to administration of the first dose of paracetamol. Furthermore, no other medications were allowed to be administered during the 3 days of the study. These factors together eliminate the possibility of drug interactions affecting the pharmacokinetics of paracetamol. Objective 2: Explain the relationship between clearance and half-life. Clearance is the removal of the drug from the body, and half-life is the amount of time it takes for the drug to reach it. .....center of paper......have decreased. When administered with probenecid, the unchanged acetaminophen concentration was significantly higher than when administered without probenecid. This is because probenecid inhibits UDPG-transferase. UDPG-transferase is a key enzyme responsible for phase 2 conjugation, so if inhibited, less acetaminophen will be converted to its metabolite acetaminophen glucuronide. This is why the clearance of that metabolite decreases when the drugs are taken at the same time. Renal elimination was decreased for both paracetamol metabolites because probenecid inhibits the active transport process in the kidneys that causes secretion of the metabolite into the tubules. Because the metabolism of acetaminophen is reduced when taken with probenecid, there is a risk of adverse effects. An increased amount of the active form of the drug in the body can lead to potential hepatotoxicity in patients.