Minor symptoms
Fatigue: symptoms is caused by decreased systemic (oxygenated blood to the rest of the body) flow. When the patient has MS and the blood flows from the left atrium to the right atrium causes the forward blood flow into the left ventricle to reduce leading to a reduction of systemic blood flow; this causes tiredness. Reduced exercise tolerance: symptoms also caused by decreased systemic (oxygenated blood to the rest of the body) flow. Just as with fatigue, when the patient has MS and the blood flows from the left atrium to the right atrium, the forward blood flow into the left ventricle is reduced leading to a reduction of systemic blood flow; this causes tiredness and hence a reduced exercise tolerance. Weight gain: this is commonly found in patients with large ASD and can be a symptom of developing right-sided heart failure. As there is a chronically increased left-to-right blood flow through the atria, this will lead in the future to right-sided heart failure. Ankle edema: This is also caused by a large ASD and has the same symptoms and causes as seen in weight gain and right upper quadrant pain. As blood flow is not happening correctly and the heart is pumping under strain, pooling of blood and fluid will happen in the ankles. Right upper quadrant pain: Also caused by large ASD; has same symptoms and underlying causes as weight gain and ankle edema. Ascites: Ascite is known as abnormal buildup of fluid in spaces between abdomen lining and abdominal organs.
Distribution
Irinotecan is a hydrophilic compound with a large volume of distribution (400 L/m2). At physiological pH, irinotecan and its active metabolite ethyl-10-hydroxy-camptothecin (SN-38) are present in two pH-dependent equilibrium isoforms; the anti tumor active lactone ring which hydrolyzed to the carboxylate isoform.In plasma, the majority of irinotecan and SN-38 are bound to albumin, which stabilizes their lactone forms. In blood, irinotecan and SN-38 are bound to platelets and red blood cells.Irinotecan has a linear pharmacokinetic. Population pharmacokinetic models assumed a three-compartmental model for irinotecan and a two-compartmental model for SN-38.SN-38 has a short distribution half-life (approximately 8 min). It reached its peak plasma concentration within 2 h after infusion. Also SN-38 exhibit a second peak in the plasma concentration because of its enterohepatic re-circulation and its release from erythrocytes. Metabolism
Activation by carboxylesterases and butyrylcholinesteras
About 2–5% of the pro-drug irinotecan is hydrolyzed into its active metabolite SN-38 in the liver by two carboxylesterase converting enzymes (CES1 and CES2) and in plasma by butyrylcholinesterase (hBChE). CES2 has a 12.5-fold higher affinity for irinotecan than CES1. While, butyrylcholinesterase has a 6-fold higher activity for irinotecan than CES. After conversion, SN-38 is actively transported to the liver by the organic anion transporting polypeptide (OATP) 1B1 transporter. Inactivation by uridine diphosphate glucuronosyltransferases
SN-38 is inactivated by glucuronidation to SN-38G (β-glucuronide conjugate) by several uridine diphosphate glucuronosyltransferase enzymes (UGTs) in the liver (UGT1A1, UGT1A9) and extra-hepatic (UGT1A1, UGT1A7, UGT1A10) and excreted into the bile. Several UGT polymorphisms affects irinotecan pharmacokinetics, for example, the decreased UGT1 activity, may lead to severe toxicity.