BIOE 425/625 Pharmaceutical engineering

Spring 2004

Homework 5

Due March 25

1. (30)You are conducting an animal study where you give an IV bolus injection of 50 mg at the initial time followed by another bolus of 20 mg at 10 minutes. Meanwhile you have a maintenance infusion of 5 mg/min that you started simultaneously with the first injection and runs for 2 hours (the whole study).

Use SAAM and model this system with a 2-compartment model (like in the tutorial). Graph the data and fitted data. What are your rate constants and the Volume of distribution.

Hint: You anticipate a Vd of 30 and rate constants between 0.001 and 0.1 min^-1

plasma data

Time (minutes)	Concentration (mg/L)
1	1.64
2	1.5
4	1.5
10	2.2
20	2.0
40	2.4
60	2.8
80	3.0
120	3.9

2. (20pts) Following a 5 mg IV bolus of a chemotherapeutic drug, a number of blood samples were collected over a period of time and analyzed via HPLC for drug plasma concentration. It was determined that this drug followed a first order, two compartmental pharmacokinetic model. Analysis of the data using “feathering”, or method of residuals, yielded the following equation.

What are Vd (initial), kel, k12, and k21 for this drug?

3 (30 pts) Four girlfriends (Anna, Brenda, Carla, and Donna) have just finished their last Bioengineering final exam and have decided to celebrate and/or commiserate over drinks at Benjy’s bar. The previous month Anna attended a MADD (mothers against drunk driving) alcohol awareness session and had her blood alcohol content as a function of time measured with a breathalyzer. In her pharmaceutical engineering class, she determined that her alcohol metabolism can be described by 1^st order adsorption in the GI (ka, rate constant of 10 h^-1) accompanied by zero order enzymatic elimination with a rate constant, ke, of 0.192g/h*L of body fluid. Anna, Brenda and Carla all have about the same alcohol metabolism, while Donna may different due to their diligent and conscientious beer bike training. Assume that the friends all weigh about the same (60 Kg), have a density of 1 g/cc and have a volume of distribution for ethanol of 40 L.

ka ke

A ® B®C

1. Anna entered the bar and immediately proceeds to do 3 shots of tequila at one time (she thinks she may just blown her last final). She starts to feel queasy and does not drink anything else for the rest of the night (3 hours). Calculate and graph the blood alcohol content (BAC) as a function of time for Anna assuming that each shot contains 20 g of alcohol.
2. Brenda orders sour apple martinis and drinks them at a very uniformed rate of 1 drink/hour. Calculate and graph the blood alcohol content as a function of time for Brenda assuming that each martini contains 40 g of alcohol and she drinks for 3 hours.
3. Carla loves to drink cosmopolitans and drinks them very quickly. She orders 1 every 30 minutes and downs them immediately. Her alcohol metabolism is easily saturated and can be modeled by zero order enzymatic degradation with a rate constant, ke, of 0.192g/h*L of body fluid since she hasn’t eaten anything, you can assume that ka>>ke. She jokes to her friends that she is undergoing a multiple dose therapy protocol. Calculate and graph the blood alcohol content as a function of time for Carla assuming that each drink contains 20 g of alcohol and she takes her last drink at 3 hours.
4. Donna is a beer drinker. She drinks a beer at a constant rate for the 3 hours the girls are at the bar and finishes 8 beers during this time (10 g of alcohol in each beer). Donna’s metabolism is not easily saturated by alcohol and the pharmacokinetics of ethanol for Donna are more likely described by a Michaelis Menten model than zero order kinetics with a maximum rate of metabolism (Vm) of 10 g/hr and the Michaelis constant (Km) of 100 mg/L. What is Donna’s BAC at 3 hours assuming that she hasn’t eaten anything all day and her alcohol absorption is immediate?

e. Are any of the girlfriends under the legal blood alcohol concentration (BAC) limit in Texas of 0.08 (800mg/L) after 3 hours in the bar?

4. (20) You are a supervisor for a pharmaceutical testing group. One of your technicians comes to you with data that he doesn’t understand. He has found an abrupt increase in the dissolution rate for the tablets that were stored for 3 months in the highest temperature in the accelerated stability cabinets. You do not have any longer time studies and all of the early and lower temperature stability studies exhibited dissolution rates that were consistently about ½ the rate of this data set. Your tablets are a very simple direct compression formulation with no coating or granulation steps.

What do think might be happening with your drug or dosage form? What experiments do you suggest to prove your hypothesis?