Biopharmaceutics and Pharmacokinetics

 

Course Code: 1002235

Credit: 6.0

Curriculum Schedule: Fall Semester                      

Instructor: Jiangeng Huang, Ph.D.Associate Professor of Pharmaceutical Sciences

No. 2 Pharmacy Building211                       

027-83650723                                

jiangenghuang@hust.edu.cn

 

Luqin Si, Ph.D. Associate Professor of Pharmaceutical Sciences  

No. 2 Pharmacy Building220                       

027-83657550                                

slq007@163.com

Office Hours: Arranged by appointment.

 

Required Materials

(1) Textbook: Basic Pharmacokinetics by Mohsen A. Hedaya; CRC Press, Taylor and Francis Group; ISBN: 1-4200-4671-3. Additional readings will be posted on line or provided in lecture as necessary.

(2) Calculator: Scientific calculator that performs logarithmic and exponential functions, and computes > 2.0 point linear regression.

 

Optional Textbooks

Concepts in Clinical Pharmacokinetics, 5th edition.DiPiro JT, et al. American Society of Health-System Pharmacists; ISBN 978-1-58528-241-8

Applied Biopharmaceutics and Pharmacokinetics, 5th edition.Shargel L, et al. McGraw-Hill; ISBN-13: 978-0-07-137550-4

 

Course Description

This course involves the fundamental study of the kinetics of drug absorption, distribution, metabolism and elimination (ADME). It is an introductory course to the basic principles and concepts of pharmacokinetics (PK) and the corresponding mathematical relationships. Students will calculate PK parameters from plasma and urine concentration data, interpret PK drug information, and use PK information to design or modify dosing regimens for individual patients. Major topics include the PK of IV bolus, oral dosing, IV infusion, multiple IV and oral dosing, multi-compartment models, hepatic and renal elimination, non-linear kinetics and therapeutic drug monitoring.

 

The course is taught primarily in lecture format, with in-class and homework problem solving cases as appropriate. There will be an optional discussion session. This discussion session will provide an excellent opportunity for student’s to ask questions regarding lecture material and in-class/homework problem sets.

 

Course Outcomes

After successful completion of this course, a student will be able to:

•     Define, explain, and differentiate fundamental principles and functionally dependent relationships of primary PK parameters.

•     Calculate common PK parameters from plasma and/or urine data after single and multiple IV or oral dosing administration.

•     Design appropriate dosing regimens based on population and patient specific PK information.

•     Predict effects of route and method of drug administration on plasma levels, using individual or population PK data, and recommend changes as needed.

•     Predict effects of drug interactions, disease states, and special populations on drug PK and modify dosage regimens appropriately.

 

Assessment

There will be one final examination at the end offall semester, worth 50% of the course grade. Exam formatting will include multiple-choice questions and PK parameter calculation questions. Students will be provided with an equation sheet during final exam, and will not be required to memorize equations; however, students will be responsible for selecting (and possibly manipulating) the proper equation and applying that equation to solve a particular problem(s).Homework assignments will be assigned for practice and will also be graded. Both homework and attendance are worth 30% of the course grade. In addition, three PK experiments will be performed and lab reports are required, worth 20% of the course grade.

Grading Scale

Course grades will be determined on the scale of 0-100.The total score below 60 is considered as failed. Only the final score will be rounded to the nearest integer to determine the final grade.There will be one make-up exam granted in this course. Students who fail in the final exam will attend the make-up exam. Also, students with an instructor-excused absence from an exam will be allowed to take this make-up exam.Instructor-excused absences are a documented illness, family emergency or participation in an official University-sponsored activity. In all instances, the student must notify the instructor prior to the exam or as soon as possible. All other absences will be considered unexcused and will result in a score of zero for that exam.

 

Academic Honesty

All University and College policies regarding student and teacher conduct and academic integrity apply to this class. The College's Honor Code Policy may be found in the Handbooks & Policies area linked at www.hust.edu.cn.

 

Special Accommodations

Reasonable accommodations will be provided for students with documented physical or learning disabilities. Please make your needs known to the instructor as soon as possible.

Electronic Devices

Use of laptop computers and handheld electronic devices (i.e. phones, PDAs, iPods, etc) is permitted in class during specified times to assist learning. Any use of any device that leads to distraction from the learning for other students will not be tolerated. Inappropriate use may include viewing online content not related to the class (including social networking sites), text messaging, answering phone calls, viewing video, and listening to music on such devices. Repercussions for inappropriate use are at the discretion of Dr. Jiangeng Huang or Dr. Luqin Si and may include (but are not limited to) dismissal from the class session, temporary confiscation of the device, and/or reporting the incident as an Honor Code violation.

 

Class Materials

Class materials, including lecture handouts, in-class problem sets, homework problem sets, equation sheets and supplementary readings, will be posted on online. In accordance with the HUST green-initiative, it is the student’s responsibility to bring the appropriate materials to lecture since Dr. Huang and Dr. Si will not provide hard-copies.

 

Teaching Arrangement

Chapter

Topic

Instructor

Class hours

Chapter 1

Introduction to PK

Dr. Luqin Si

2

Chapter 2

Single IV Bolus

Dr. Luqin Si

8

Chapter 6

Continuous IV Infusion

Dr. Luqin Si

4

Chapter 7

Multiple IV Bolus

Dr. Jiangeng Huang

8

Chapter 3

Drug absorption following oral administration

Dr. Jiangeng Huang

8

Chapter 4

Oral PK: Rate of drug absorption

Dr. Jiangeng Huang

8

Chapter 5

Oral PK: Extent of drug absorption

Dr. Jiangeng Huang

6

Chapter 8

Renal Elimination

Dr. Jiangeng Huang

8

Chapter 9

Hepatic Clearance

Dr. Jiangeng Huang

8

 

Review class

Dr. Jiangeng Huang

4

Experiments

 

 

 

1

Rat Intestinal absorption of Sulfadiazine Sodium by single-pass intestinal perfution

Dr. Jiangeng Huang

10

2

IV PK of Acetaminophen in rabbits

Dr. Jiangeng Huang

12

3

Distribution of Sulfadiazine Sodium in mice

Dr. Jiangeng Huang

10

 

FINAL EXAM:  50%

 

 

 


 

 

Chapter 1  Introduction to Biopharmaceutics and Pharmacokinetics

  • Teaching contents:

1.1 Introduction

1.2 Application of biopharmaceutic and pharmacokinetic principles in biomedical fields

1.3 Drug concentration-time profile

1.4 Linear and nonlinear pharmacokinetics

1.5 Pharmacokinetic modeling

1.6 Pharmacokinetic simulation

  • Teaching key and difficult points

1.Key points: the definition of biopharmacokinetics, biopharmaceutics, linear and nonlinear pharmacokinetics,etc.

2.Difficult points: application of pharmacokinetics,the characteristics of zero-order,first-order pharmacokinetics

  • Course assessment requirements

1.To define pharmacokinetics (PK), pharmacodynamics (PD), and clinical pharmacokinetics; and understand the similarities and differences between these topics?

2.To describe the basic differences between linear and nonlinear PK

  • Review questions:

1.What is the difference between pharmacokinetics and pharmacodynamics ?

2.What is meant by the pharmacokinetics parameter ?

3.Please describe the major differences between linear and nonlinear pharmacokinetics.


 

 

Chapter 2  Drug pharmacokinetics following single intraveneous administration

  • Teaching contents:

2.1 Introduction

2.2 Elimination rate constant

2.3 Volume of distribution

2.4 Half-life

2.5 Total body clearance

2.6 Area under the curve

2.7 Factors affecting the drug blood concentration-time profile

  • Teaching key and difficult points

1.Key points: determination of several pharmacokinetic parameters such as the first-order elimination rate constant k, volume of distribution Vd, half-life t1/2, total body clearance ClT, area under the curve AUC.

2.Difficult points: to understand how the different pharmacokinetic parameters affect the drug profile in the body and the clinical importance of those pharmacokinetic parameters

  • Course assessment requirements

1.To determinine the phamacokinetic parameters after a single IV drug administration.

2.To analyze the effect of changing one or more of the phamacokinetic parameters on the plasma C-t profile after a single IV drug administration.

3.To utilize the mathematical expression to calculate the plasma concentration at any time after a single IV drg administration.

4.To calculation the appropriate IV dose required to achieve a spectific drug concentration.

  • Review questions:

1.Cefamandole is a 2nd generation cephalosporin that is eliminated from the body by first-order kinetics.  Your patient is administered 1.0 gram cefamandole by IV bolus.

a) Predict the amount of drug remaining in the body 3 hours after administration assuming a 1st order elimination rate constant (k) is 0.81 hr-1.

b) After clinical laboratory tests, you determine that the amount of cefamandole remaining in the patient after 3 hours is actually 200 milligrams.  Calculate the actual elimination rate constant.

c) Using this new information, calculate the time required for the amount of cefamandole in the body to decrease to 125 mg after a 1.0 g IV bolus dose.

d) Calculate an appropriate IV bolus dose to maintain 300 mg of the drug in the body 4 hrs post-dose.

2.After administration of  a single 400 mg IV bolus dose of a drug, a plot of the blood concentration-time profile on semilog graph paper is linear with a slope of - 0.1 hr-1, and y-intercept of 1.0 mg/L.

a. Calculate k for this drug.

b. Calculate half-life for this drug.

c. Calculate Vd for this drug.

d. Calculate CLT for this drug.

e. Calculate AUC for this drug.

f. What are the slope and y-intercept if the dose was 1000mg?

g. What’s the length of time requires for the initial drug concentration to decrease to 0.25mg/L after administration of the 400 mg dose?

h. What’s the smallest dose required to achieve a blood drug concentration above 1mg/L for 6 hr after administration?

Chapter 3Drug Absorption Following Oral Administration: Biopharmaceutical Considerations

  • Teaching contents:

3.1 Introduction

3.2 Physiological factors affecting oral drug absorption

3.3 Physical factors affecting oral drug absorption

3.4 Dosage form characteristics

  • Teaching key and difficult points

1.Key points: oraladministration, transmembrane transport, gastrointestinal physiology, oral dosage forms, in vitro test,etc.

2.Difficult points: to understand how variousthe physiological and physical factors affect oral drug absorption, to understand how the different oral dosage forms behave within the GIT lumen.

  • Course assessment requirements

1.To describe the different mechanisms for drug absorption after oral administration

2.To describe how the gastrointestinal tract (GIT) physiology and physiochemical drug properties affect the absorption of drugs after oral administration

3.To describe the factors that affect drug dissolution after oral drug administration and recommend approaches to improve drug dissolution and hence drug absorption

4. To analyze the different factors that can affect the drug absorption and recommend the strategies that can improve drug absorption

  • Review questions:

 

A single dose of 500mg of an antibiotic was given as an oral tablet to a 70-kg patient.  The concentration-time profile can be described by the following equation:

­C­p=10 ( e-0.154t – e-0.954t )

Where C­pis in milligrams per liter, t is in hours, and the drug is completely absorbed.

  1. Calculate the elimination half-life of this drug.
  2. Calculate the volume of distribution of this drug.
  3. Calculate he total body clearance of this drug.
  4. Calculate tmaxand C­max.
  5. Calculate the AUC after administration of a 500-mg oral dose.
  6. Calculate the plasma concentration 4hr after drug administration.
  7. What’s the plasma concentration equation after administration of a 100-mg oral dose.

 

 


 

 

Chapter 4DrugPharmacokinetics Following Single Oral Drug Administration: Rate of Drug Absorption

  • Teaching contents:

4.1 Introduction

4.2 Drug absorption after oral administration

4.3 Plasma concentration-time profile after a single oral dose

4.4 Determination of absorption rate constant

4.5 Clinical importance of absorption rate constant

4.6 summary

  • Teaching key and difficult points

1.Key points: the kinetics of drugs absorption, the characteristics of plasma concentration-time profile after a single oral dose,absorption rate constant, etc.

2.Difficult points: the different phase in plasma concentration-time profile, the methods to determine absorption rate constant.

  • Course assessment requirements

1.To describe how the rate and extent of drug absorption after oral administration affect the onset and the duration of drug effect

2.To calculate the drug half-life after oral administration

3. To analyze how the change in the absorption rate constant affects the plasma concentration-time profile after a single oral administration

4. Estimate the absorption rate constant utilizing the method of residuals and the Wagner-Nelson method

  • Review questions:

1. Consider Drug X, which has Vd =10 L and an elimination rate constant = 0.1/hr.  Five different 100 mg oral tablets are developed, each with a different dissolution rate and thus a different absorption rate. The bioavailability from all the tablets is 100%.

Listed below are the first-order absorption rate constants for the five tablet formulations.

Formulation 1            ka = 0.2/hr

Formulation 2            ka = 0.3/hr

Formulation 3            ka= 0.4/hr

Formulation 4            ka = 0.5/hr

Formulation 5            ka = 0.6/hr

 

Calculate the Cmax, tmax and AUC for each of the formulations. What conclusions can you draw about the effect of absorption rate on these parameters?

 

2. Consider Drug Y with a Vd = 10 L and an oral dose of 100 mg. The oral tablet has 100% bioavailability, and has an absorption rate constant = 0.301/hr. This tablet is dosed to 5 patients with different clearances, so that the elimination rate constant is different in each patient as follows:

Patient 1              k = 0.1/hr

Patient 2              k = 0.2/hr

Patient 3              k = 0.3/hr

Patient 4              k = 0.4/hr

Patient 5              k = 0.5/hr

Calculate the Cmax, tmax and AUC for this tablet in each of the patients. What conclusions can you draw about the effect of elimination rate on these parameters?

 

3. A single oral dose of 300 mg was given to an adult male patient (72 kg; Vd= 0.083 L/kg). From the literature, the PK of this drug fits a one-compartment model. The equation of the line that best fits the PK of this drug is:

Assume the units are mg/mL for concentration and 1/hr for the rate constants. Calculate Cmax, tmax and t1/2 in this patient, and the bioavailability of the oral product.


 

 

Chapter 5DrugPharmacokinetics Following Single Oral Drug Administration: Extent of Drug Absorption

  • Teaching contents:

5.1 Introduction

5.2 Purpose of bioavailability and bioequivalence studies

5.3 Causes for variation in drug bioavailability

5.4 Pharmacokinetic basis of drug bioavailabilityand bioequivalence

5.5 Determination of drug bioavailability

5.6 Calculation of area under the curve

5.7 Regulatory Requirements for bioavailabilityand bioequivalence

5.8 Factors affecting the blood concentration-time profile after a single oral dose

  • Teaching key and difficult points

1.Key points: the definition of bioavailability and bioequivalence, factors affecting drug bioavailabilitybiopharmaceutics,first-pass effect,linear trapezoidal rule,design and evaluation of bioequivalence, etc.

2.Difficult points: to understand how the different factors affect the bioavailability, the changes of pharmacokinetic parameters after taking bioavailability into consideration, to understand how the different factors affect the blood concentration-time profile after a single oral dose.

  • Course assessment requirements

1.To define the bioavailability and the bioequivalence of drug products

2.To describe the different components of the firs-pass effect after oral drug administration

3. To determine the absolute bioavailability and relative bioavailability of oral drug products

4. To calculate the area under the curve (AUC) using the trapezoidal rule

5. To describe the general principles for designing and evaluating bioavailability and bioequivalence studies

6. To analyze the effect of changing the drug pharmacokinetic parameters on the plasma concentration-time profile after oral drug administration

  • Review questions:

A 500 mg oral tablet of Fitchamicin was given to an 80 kg male, and plasma concentrations were measured as follows:

 

Time (hr)      Conc.(mg/L)                      Time (hr)      Conc.(mg/L)

0.25              3.73                            3.0         3.85

0.5         5.92                                   4.0         2.22

1.0         7.45                                   5.0         1.23

1.5         7.13                                   6.0         0.669

2.0         6.10                                   8.0         0.193

 

When a 500 mg dose of Fitchamicin was administered by IV bolus, the following plasma concentration data were obtained:

 

Time (hr)             0.25              1.0         2.0         4.0

Conc. (mg/L)              15.0              9.16              4.88              1.29

 

  1. Plot the po and IV data on a single semi-log plot.
  2. From the graph, estimate the Cmax and tmax after po dosing.
  3. Calculate k and t1/2 for the drug after IV dosing using linear regression.
  4. Calculate k, y-intercept, and t1/2 after po dosing. Use linear regression and the last 4 data points.
  5. Construct a residuals table (Cextrapolated -Cmeasured).
  6. Plot the residuals versus the corresponding time as a semi-log plot. Calculate the absorption rate constant ka and the corresponding y-intercept using linear regression.
  7. Calculate the absolute bioavailability of Fitchamicin after oral dosing. You will need to determine AUCpotrapezoidally, and AUCIVeither trapezoidally or from a suitable equation.
  8. Calculate volume of distribution using both IV and po data. How do they compare?
  9. Calculate tmaxand Cmax using values of k, ka and Vd that you’ve calculated. How do these compare to the estimates from the graph?
  10. Calculate the total body clearance of Fitchamicin after IV and po dosing. Use both equations. Express CLT in mL/min.
  11. If you only had plasma concentration data for po administration but not for IV administration, which kinetic parameters that we’ve calculated above could you determine? Which kinetic parameters could NOT be determined?


 

 

Chapter 6Steady-state principle and drug pharmacokinetics

  • Teaching contents:

6.1Introduction

6.2 Plasma concentration during continuous constant-rate IV drug administration

6.3 Time required to reach steady state

6.4 Loading dose

6.5 Determination of the pharmacokinetic parameters

  • Teaching key and difficult points

1.Key points: determination of several pharmacokinetic parameters such as the first-order elimination rate constant k, volume of distribution Vd, total body clearance ClT, and recommend an appropriate IV loading dose and IV infusion rate k0 to achieve specific steady-state plasma concentrations.

2.Difficult points: the factors which affect the time required to reach steady state, and the effect of changing one or more of the pharmacokinetic parameters on the steady-state plasma concentration during constant-rate IV infusion.

  • Course assessment requirements

1.To determine the steady-state drug concentration and the pharmacokinetic parameters during constant-rate IV infusion.

2.To analyze the effect of the changing one or more of the pharmacokinetic parameters on the steady-state plasma concentration during constant-rate IV infusion.

3.To recommend an appropriate IV loading dose and IV infusion rate to achieve specific steady-state plasma concentrations.

  • Review questions:

1. What SS concentration do you expect for an anti-viral drug (k=0.025 hr-1; Vd= 15 L) dosed by IV infusion at a rate of 10 mg/hr?

2. An antibiotic has a Vd=10 L and k=0.2 hr-1.  The desired SS concentration is 10 µg/mL. What infusion rate would you recommend?

3. The patient shows an adverse effect, and you decide to decrease the SS concentration to 7 µg/mL. What new infusion rate is needed?

4. What is the main reason for giving a drug by slow IV infusion?

5. Why do we use a loading dose to rapidly achieve therapeutic concentration for a drug with a long elimination half-life, instead of increasing the rate of drug infusion or increasing the size of the infusion dose?

6. What are some of the complications associated with IV infusion?

7. At steady state when equilibration is reached between plasma and the tissue, are the plasma and tissue levels equal?

Chapter 7Steady State during Multiple Drug Administrations

  • Teaching contents:

7.1 Introduction

7.2 Drug plasma concentration-time profile during multiple drug administrations

7.3 Average plasma concentration at steady state

7.4 Time required to reach steady state

7.5 Loading dose

7.6 Drug administration

7.7 Controlled-release formulations

7.8Effect of changing the pharmacokinetic parameters on steady-state plasma concentration during repeated drug administration

7.9 Dosage regimen design

  • Teaching key and difficult points

1.Key points: the definition of steady state andloading dose,the pharmacokinetics during multiple drug administration, dosage regimen design, etc.

2.Difficult points: to calculate the time required to reach steady state, to understand the effect of changing the pharmacokinetic parameters on steady-state plasma concentration during repeated drug administration and factors to be considered while designing a drug regimen.

  • Course assessment requirements

1.To define the steady state during multiple drug administrations

2.To identify the factors that affect the steady-state plasma concentration during multiple drug administrations

3. To determine the steady-state drug concentration and patients’ pharmacokinetic parameters during multiple drug administrations

4. To analyze the effect of changing one or more of the pharmacokinetic parameters on the steady-state plasma concentration during multiple drug administrations

5. To recommend the dosing regimen to achieve specific plasma concentrations in patients

6. To evaluate the appropriateness of certain dosing regimens for patients

  • Review questions:

A drug has a therapeutic range of 0.5-1.0 mg/mL. A 30 mg dose of this drug was administered to a patient by IV bolus, and the following plasma concentrations were obtained after the first dose:

                   Time (hr)                Plasma Conc. (mg/mL)

 

  1. 0.688

4                         0.531

 

The multiple dose regimen recommended by the physician is to administer 30 mg of the drug every 12 hours to this patient. You are asked to comment on the appropriateness of this regimen, and to recommend changes, if necessary. Assume a one-compartment model, first-order elimination.

 

Proceed step-by-step, and answer the following questions.

1. What are the PK parameters (elimination rate constant and half life, volume of distribution, and total body clearance) of this drug in this patient?

2. What are the maximum (Cpmax) and minimum (Cpmin) concentrations after the first dose?

3. What are the Cpmaxand Cpmin after the second, third, fourth and fifth doses?

4. Are the steady state peak and trough values within the therapeutic range?

5. What is the accumulation factor, Raccum, at SS?

6. If 30 mg of the drug had been administered every 24 hours instead of every 12 hours, would Raccumbe higher or lower? Calculate Raccum for this regimen.

7. If the drug had been administered every 48 hours, what would Raccum be?

8. What is the average SS concentration for the regimen recommended by the physician (30 mg of drug dosed at 12 hour intervals)?

9. What is the fluctuation between the peak and trough concentrations at SS with the physician’s regimen?

10. With the physician’s regimen, SS peak and trough concentrations are outside the therapeutic window, which is undesirable. We would like to change the regimen to bring these values within the therapeutic range while maintaining the same average SS concentration. What changes would you make to accomplish this?

11. Further pharmacodynamic evaluation indicates that this patient responds to higher plasma levels than the average population, without any significant adverse events. The desired peak plasma level is now 1.2 mg/L, and the desired dosing interval is 6 hr. Calculate the new dose that needs to be given at 6 hr intervals.

Chapter 8Renal Drug Elimination

  • Teaching contents:

8.1 Introduction

8.2 Mechanisms of renal excretion rate

8.3 Determination of renal excretion rate

8.4 Renalclearance

8.5 Cumulative amount of the drug excreted in urine

8.6 Determination of pharmacokinetic parameters from renal excretion rate data

8.7 Effect of changing the pharmacokinetic parameters on urinary excretion of drugs

  • Teaching key and difficult points

1.Key points: renal drug elimination, renal excretion rate, renal clearance,pharmacokinetic parameters from renal excretion rate data etc.

2.Difficult points: to know how to calculate renal clearance and how to determine pharmacokinetic parameters from renal excretion rate data, to understand how the different factors affect the pharmacokinetic parameters on urinary excretion of drugs

  • Course assessment requirements

1.To discuss the mechanisms of renal drug excretion

2.To determine the drug pharmacokinetic parameters from the urinary excretion rate data

3. To calculate the renal clearance of drugs from the urinary excretion rate data

4. To analyze the effect of changing the dose total body clearance, and renal clearance on the urinary excretion of drugs

5. To predict the change in the overall elimination rate of drugs caused by the change in their renal excretion

  • Review questions:

Ranitidine has a total body clearance of 10.4 mL/min/kg and a volume of distribution of 1.3 L/kg. It is eliminated both hepatically and renally, with a fraction excreted  unchanged = 0.7 in patients with normal kidney and liver function. The minimum effective plasma concentration of ranitidine for suppression of basal acid secretion          is 100 ng/mL. The bioavailability of ranitidine tablets is 52%.  Estimate the following PK parameters in a 70 kg patient with normal hepatic and renal function:

 

  1. Plasma half-life and elimination rate constant
  2. Fraction of the drug metabolized in the liver
  3. Renal clearance and hepatic clearance
  4. Renal and hepatic elimination rate constants
  5. The average SS concentration after administration of 150 mg twice daily. Is this concentration therapeutic?

 

Ranitidine is given to a 70 kg patient with normal hepatic function, but with renal dysfunction resulting in a renal clearance that is one fourth of normal. Assume that the volume of distribution does not change. Estimate:

  1. Renal, hepatic and total clearance
  2. Fraction of drug eliminated renally and hepatically
  3. Elimination rate constant and half-life
  4. Renal and hepatic elimination rate constants
  5.  The average SS conc after dosing 150 mg twice daily dosing
  6. A new dose to produce the same average SS conc as the normal patient above


 

 

Chapter 9Physiological Approach to Hepatic Clearance

  • Teaching contents:

9.1 Introduction

9.2 Organ clearance

9.3 Hepatic extraction ratio

9.4 Intrinsic clearance (CLint)

9.5 Systemic bioavailability

9.6 Effect of change in intrinsic clearance and hepatic blood flow on hepatic clearance, systemic availability, and drug concentration-time profile

9.7 Protein binding and hepatic extraction

  • Teaching key and difficult points

1.Key points: the definition oforgan clearance hepatic extraction ratio, intrinsic clearance, systemic bioavailability,factors affecting systemic availability and hepatic clearance, etc.

2.Difficult points: to understand how the change in intrinsic clearance and hepatic blood flow affect hepatic clearance, systemic availability, and drug concentration-time profile

  • Course assessment requirements

1.To describe the physiological meaning of the total body clearance in terms of organ blood flow, intrinsic clearance, and excretion ratio

2.To describe the effect of changing the hepatic intrinsic clearance and blood flow on the efficiency of the liver to eliminate the drug (extraction ratio)

3. To analyze the effect of changing the intrinsic clearance on the plasma concentration-time profile after intravenous (IV) and oral administration

4. To analyze the effect of changing the liver blood flow on the plasma concentration-time profile after IV and oral administration

  • Review questions:

I.  Cimetidine has an absolute oral bioavailability of 0.7, and a hepatic clearance of       210 mL/min in subjects with normal hepatic function. Answer the following questions, assuming that hepatic blood flow is 1.5 L/min.

 

  1. Calculate the hepatic extraction ratio EH.
  2. Is the oral bioavailability of cimetidine consistent with this extraction ratio? Where else can the drug be lost after oral dosing?
  3. Estimate the intrinsic clearance of cimetidine, assuming 20% of the drug is bound to plasma proteins.

 

II.  A new drug PK1598 is eliminated entirely by biotransformation.  After IV bolus administration, the total body clearance was estimated from the dose and the measured AUC, and found to be 85 L/hr.  The volume of distribution of PK1598 is 400 L.  Assume hepatic blood flow to be 1.5 L/min.

  1. Calculate k and t1/2 of PK1598.
  2. What is the hepatic clearance of PK1598?
  3. Estimate the hepatic extraction ratio. Is this a low or high extraction ratio drug?
  4. Estimate the intrinsic clearance if the reported fraction of unbound drug in plasma is 10%. Is hepatic blood flow or intrinsic clearance rate-limiting in the hepatic clearance of PK1598?
  5. PK1598 was co-administered with cimetidine, which is known to inhibit the metabolism of PK1598. Cimetidine decreases the intrinsic clearance of PK1598 by a factor of two.  Estimate the hepatic clearance, extraction ratio, elimination rate constant and half-life of PK1598 under these conditions.  Comment on the changes, if any, of these parameters.
  6. PK1598 is administered with a drug that increases cardiac output, resulting in a two-fold increase in hepatic blood flow. Assuming that intrinsic clearance, Vd and free fraction of drug in plasma remain the same, estimate hepatic clearance, extraction ratio, elimination rate constant and half life of PK1598 under these conditions.  Comment on the changes, if any, of these parameters.
  7. PK1598 is administered with a drug that displaces it from plasma protein-binding sites; the free fraction of PK1598 increases to 0.5. Estimate how hepatic clearance and extraction ratio of PK1598 will change in this situation.