BIOE 425/625  Homework 4

 

Due March 11, 2003

Chemistry & absorption, infusion

 

  1. (25 pts)Determine whether or not these drugs will have absorption issues using Lipinski’s rule of 5.  You can use http://www.logp.com/ if you would like.

a.  Clonidine  (Catapres)

 

b  Accutane (isoretinoin)

 

 

 

 

 

  1. Doxorubicin (adryamicin)

 

d  AZT

  1.  Diazepam (valium)

2  (5 pts) phenytoin is a drug used for epilepsy.  It is acidic with pKA of 8.1 and the unionized species is not water soluble.  It is usually administered via infusion at 50 mg/min.  Would it be ok if, for convenience, a nurse, diluted phenytoin sodium solution with a bag of IV fluid (pH 4.5)?  Why or why not?

 

 

3 (20 pts) A beaker is separated in half by a membrane into two compartments A and B.      A weakly acidic drug with a pKa of 3 is dissolved in compartment A of the beaker.  Compartment B has a pH of 4  and we do not know the pH of compartment A.  Since the drug in A cannot escape the beaker and nothing is reacting  Caintital = Ca(t) +Cb(t) at any time.  Only nonionized drug can pass through the membrane. 

 

Time (min

Total concentration (mg %) in compartment A

0

6.6

5

4.14

10

2.69

15

1.89

20

1.32

30

0.85

40

0.68

50

0.63

60

0.61

70

0.6

80

0.6

90

0.6

 

A.              Calculate the apparent 1st order rate constant for the disappearance

 of A (i.e. ln( Ca-Cinfinite) vs time)

 

B.              What is the apparent equilibrium constant (K= [B infinty]/[ A infinity]) 

 

 

 

C         What is the value of the equilibrium constant (K) if only the concentration of unionized drug is considered?  (Think about  what can and cannot be transported across the membrane and what happens to the driving force for passive diffusion at equilibrium).

 

 

D         What is the pH of compartment A at equilibrium?

 

 

  1. (20)What is controlling the rate of absorption of a 325 mg enteric coated aspirin tablet – the dissolution rate or the membrane absorption rate?    Enteric coatings like Eudragit L 30 D-55 (a methacrylic acid copolymer) do not dissolve in acidic conditions and function to either protect the stomach from the drug or to protect the drug from the acidic stomach fluids.  In this case, Eudragit L 30 D-55 only dissolves  above pH 5.5 but above this pH it dissolves very rapidly.   Therefore, with this formulation, aspirin is only absorbed through the duodenal and jejunum  epithelium (pH = 6.0 surface area = 33m2)  via passive absorption.  Aspirin has a molecular weight =180 Da, Diffusion coefficient in water of 2 x10‑5 cm2/s, Solubility= 1g/300ml, pKa=3.9 and membrane permeability of 10-6 cm/s .   Assume the effective surface area of the tablet is described by pr2 where r=0.5 cm and the film thickness h=0.01cm. 

Aspirin

 

 
 
 

5. (10 pts)A  cancer patient is being treated with chemotherapeutic drug in a clinical setting.  The first dose given was a bolus IV injection of 1000 mg.  The initial plasma concentration from this dose was 5.56 mg/ml.  A few days later, the patient was started on an infusion regime with this drug with a series of infusions lasting 30 minutes of 1000 mg that were delivered every 8 hours.   The normal total clearance of this drug is 36 L/hr.   50% of the drug is metabolized in the liver and 50% is excreted unchanged in the urine.  Approximately 85% of the drug is bound to plasma protein and 15% is unbound.  Normal liver blood flow is 90 L/hr and the glomerulus’s flow rate is 125 ml/min. 

A.    What renal processes are important in this drug’s clearance?

B.    Calculate the elimination rate constant

C.    Predict the peak (Cp max) and trough (Cpmin) concentrations after the first short term infusion regime.

D.    How many infusions are needed to reach steady state conditions ( you can assume 5 half lives are needed)?

 

5.  (20 pts)  Read Gentamicin dosing in critically ill patients  paper.  Write a summary ( < 1 page) of their study.   You should be able to give an overview of their work (purpose, experiential procedure, findings)  and point out the strengths and weaknesses of their research.   The Nicolau paper, reference (12), is here if you are interested.