Answers Case Study 2 PHA 5127 Fall 2005 Question 1: An 50-year-old, male patient was admitted to hospital with gram-negative pneumonia infection, and was given an iv bolus of drug X. (200 mg). The drug concentrations at 2hr and 12hr after initial dose were reported as 7.1mg/L and 1.3mg/L. Assuming the drug follows one compartment body model with first-order elimination, please calculate the total Cl, AUC 0-∞, Vd, t 1/ 2 for drug X. Answer: ke = ln (C 2/ C1)/ (t1 – t2) = ln ( 1.3/7.1) / (2-12) = (-1.7 ) / (-10) = 0.17 /hr t 1/ 2 = 0.693/0.17= 4.1hr drug concentration at time zero: C0 = C1 * exp ( ke * t) = 7.1 * exp ( 0.17 * 2) = 10mg/L vd = Dose / C0 = 200 / 10 = 20 L Cl = ke * Vd = 0.17 * 20 = 3.4 L/hr AUC 0-∞ = Dose / Cl = 200/ 3.4 = 58.8 mg*hr/L Question 2: 70-90% of quinidine is bound to plasma albumin and alpha-1-acid glycoprotein. In patients with chronic liver disease plasma protein binding is decreased by 20%. How will the volume of distribution change? Use a plasma volume of 3 L and the fraction bound in plasma 80% (for normal patients), a tissue volume of 38 L and the fraction unbound in tissue 80% to calculate the volume of distribution in patients with liver disease. Answer: Vd = Vp + Vt * fu / fu, T For patients with liver disease, only fu increase, all the other factors remain unchanged, as we can see from the equation, the Vd will increase. 0.8 * 0.8 = 0.64 fu = 1-0.64= 0.36 > normal patients’ 20% free fraction Vd = 3 + 38 * 0.36/0.8 =20.1 LQuestion 3: Researchers recently found out that grape fruit juice is CYP3A4 inhibitor. When taking together with grape fruit juice, the intrinsic hepatic clearance (CL int) of drug B is decreased by 20%. Main pharmacokinetic parameters of drug B were listed as following: Hepatic clearance ( WITHOUT taking grape fruit juice), CL hep = 10 L / hr. Fraction unbound: fu = 0.4. Please calculate what is the new hepatic clearance, when drug B is taking together with grape fruit juice. Assume the hepatic blood flow is 90 L / hr. Answer: First, calculate the original CL int. CL = (QH * fu * CLint) / (QH + fu * CLint) CL = (90 * 0.4 * CLint) / (90 + 0.4* CLint) = 10 CLint = 28.125 = 28.1 L/ hr Then, calculate the new CL hep. CL = (QH * fu * CLint) / (QH + fu * CLint) = 90 * 0.4 * 28.1 * 0.8 / ( 90 + 0.4 * 28.1 * 0.8) = 90 * 8.992 / ( 90 + 8.992 ) = 8.2 L/hr Question 4: Please answer the following questions with true or false: a) for high extraction drugs: 1) In case of a increasing fraction unbound, the extraction ratio of the drug stays the same, Answer: TRUE, for high extraction drugs, E ≈ 1, independent on fraction unbound 2) In case of increased hepatic blood flow, the clearance stays the same Answer: FALSE : for high extraction drugs , CLhep = E *Q ≈ Q , when Q increase, CLhep increases b) for low extraction drugs: 1) In case of increasing fraction unbound, the extraction ratio of the drug stays the same, Answer: FALSE: for low extraction drugs, E ≈ Clint*fu / Q, when fu increase, E increases 2) In case increasing hepatic blood flow, the clearance of the drug stays the same. Answer: TRUE: for low extraction drugs, Clhep≈ Clint*fu , independent of liver blood flow
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