PHA 5127 (Fall, 2008) Case Study #1 Answers Q1. 800 mg of drug X was administrated to a patient through i.v. bolus. The drug plasma concentrations monitored after injection are listed in the table below. Time (min) Conc. (mg/l) 2 72.9 7 57.9 15 40 30 20 60 5 a) Please state whether the drug follows a zero- or a first-order elimination process. 0204060800 5 10 15 20 25 30 35 40 45 50 55 60 65Conc ( mg/ l )time ( min) Zero-order elimination process has a constant drug elimination rate. If you plot the drug concentration vs. time on an ordinary scale, you should see a straight line. This is not the case here.1101000 5 10 15 20 25 30 35 40 45 50 55 60 65Conc ( mg/ l )time ( min) If you plot data points on a semi-log scale, you can see they almost perfectly line up on straight line. Therefore, the elimination process is first-order kinetics. b) Estimate the elimination rate constant (ke) and half-life (T1/2). If you study the data carefully, you should be able to see the concentration decreases to half after 15 mins (from 40 mg/l at 15 min to 20 mg/l at 30 min) So: T1/2 = 15 min => ke = 0.693/15 = 0.0462 /min Or: ke = (ln(40)-ln(5))/(60-15)=0.0462 /min => T1/2 = 0.693/0.0462=15 min c) Estimate the initial plasma drug concentration (C0) and volume of distribution (Vd). C0=72.9*exp(0.0462*2)=80 mg/l Or: C15= 40 mg/l and T1/2 = 15 min => C0=2*C15 = 80 mg/l And Vd = D/ C0 = 800/80 = 10 L d) Estimate the initial plasma drug concentration (C0) and AUC0-inf. Use the trapezoidal rule to calculate the area under the curve from time zero to the last time point (AUC0-60). The general formula to calculate the area of a trapezoid is:AUC0-60=1/2*{(80+72.9)*2+(72.9+57.9)*5+(57.9+40)*8+(40+20)*15+(20+5)*30} = 1696.5 min*mg/l In order to calculate the area under the curve from the last time point to infinity (AUC60-inf), we need to divide the last given concentration (C60) by the elimination rate constant (ke): AUC60-inf = 5/0.0462 =108.2 min*mg/l Therefore, AUC0-inf = AUC0-60 + AUC60-inf = 1696.5 + 108.2 = 1804.7 min*mg/l e) Predict the drug plasma concentration 2 hrs after the injection (C120). C60. = 5 mg/l and T1/2 = 15 min => C120. = C60 / (2^4)= 5/16 = 0.3 mg/l Q2. Please fill in the missing numbers! 41L Extracellular Fluid Intracellular Fluid 23L 18L Plasma Water Interstitial Fluid 15L 3L Total Body Water Q3. Mark each of the following statements True or False. T F For a first-order elimination process, the same amount of drug is eliminated during a given time interval. T F For a zero-order elimination process, the half-life (t1/2) depends on the drug concentration.T F In a perfusion limited distribution, tissue membrane represents no barrier for the drug diffusion. T F In a permeability limited distribution, blood flow is not important for rate of uptake. T F Volume of distribution is the real tissue volume that contains the drug. Q4. Define the term biopharmaceutics and pharmacokinetics. Biopharmaceutics studies the influence of the dosage form of a drug on its pharmacological effect (or conc.). Pharmacokinetics studies what the body does to the drug. It describes the time course of drug and metabolite concentrations in the
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