Pharmacokinetics and Drug Metabolism
Due at Midnight tonight
1. (10 points) A drug that binds to the plasma proteins (fu=0.7) has a total body clearance of 500 mL/min, and 75% of a dose is excreted unchanged.
a. Calculate the drug’s renal clearance.
. Calculate the drug’s nonrenal clearance
c. Discuss possible processes in the kidney involved in its excretion.
d. How may its excretion be modified?
2. (10 points) A new drug under development has just undergone phase I trials to determine its human pharmacokinetics. These studies have obtained the following information:
Cl =1200 mL/min Vd=25 L/kg fu = 0.85
fe=0.05 BP=1 log D7.4 = 2
The drug is also a potent competitive inhibitor of CYP2D6. Discuss the drug’s pharmacokinetics with particular reference to:
a. Type of clearance: renal/hepatic and restrictive/nonrestrictive
. Expected bioavailability
c. Distribution characteristics
d. Elimination half-life
e. Susceptibility to drug interactions
3. (10 points) Felodipine has the following characteristics: hepatic clearance=770mL/min, BP=0.680, and fu=0.004. Use 1500 mL/min for hepatic blood flow.
a. Calculate its hepatic extraction ratio
. Calculate its intrinsic clearance.
c. Calculate its hepatic bioavailability
4. (10 points) Which of the hypothetical metabolic reactions shown in Scheme I below are Phase I and which are Phase II?
5. (5 points) What are the redox partners for Cytochrome p450 enzymes? What is their role in the catalytic process of the P450 enzymes? How are they similar and how are they different?
6. (5 points) How is UDPGA formed from glucose-1-phosphate? Describe its role in the glucuronidation process.
7. (10 points) Label all of the functional groups on the following structures.
.
c.
8. (10 points) Describe the differences between the SET and HAT mechanisms for N-dealkylation. Explain why N-dealkylation is one of the most common metabolic pathways and why it is more energetically favored than O-dealkylation. Define the differences between N-dealkylation and deamination.
9. (10 points) The following structure is metabolized into 6 major metabolites. Draw 6 reasonable metabolites for this drug.
XXXXXXXXXXpoints) How do N-oxide metabolites provide a “depot” for the active drug? Discuss any metabolic reactions involved in detail.
XXXXXXXXXXpoints) Find the structures and draw a potential glucuronide for each of the following compounds:
Acetaminophen
Chloramphenicol
Fenoprofen
Desipramine
Sulfadimethoxine
Methimazole