Multiple Compartment PK

Question 1

General Information

Answer 1

• Time course and extent of distribution and elimination of drug from body determines its disposition
• Body may be viewed as a number of kinetic compartments between which drug distributes and from which elimination occurs
• Rarely do these kinetic compartments have true physiological basis
• Blood, readily available fluid, and well-perfused tissues may be treated as a homogeneous unit known as central compartment (brain may or may not be included here depending on the lipophilicity of the drug)
• Drug levels in poorly perfused tissues (muscles, lean tissue, fat) may be treated kinetically as peripheral compartment

Question 2

Representation of Data

Answer 2

• 3 possible Models
• Always have k12 and k21
• Can leave central compartment only (k10), peripheral compartment only (k20), or both compartments (10 & 20)
• Difficult to determine which model is correct
• Most common: leaving central compartment only

Question 3

Z

Answer 3

-Number of solvable rate constants when sampling from a central compartment
Z = 2(n-1) + 1
-For a two compartment model, Z = 3, but one of the models has four rate constants

Question 4

IV: Two Compartment Model Variables

Answer 4

Xc = amount of drug in central compartment
Xp = amount of drug in peripheral compartment
k12 = transfer rate constant of central ==> peripheral
K21 = transfer rate constant of peripheral ==> central
k10 = elimination rate constant from central

Question 5

IV Assumptions

Answer 5

• Drug elimination occurring from central compartment only
• There is time required for drug to equilibriate between two compartments
• Drug elimination and distribution is governed by first order kinetics

Question 6

Order to Solve Rate Constants

Answer 6

K21 ==> K10 ==> K12

Question 7

Are lambda2 and K10 the same parameter?

Answer 7

No. Lambda includes both distribution and elimination while K10 is only elimination from the central compartment.

Question 8

Vc - IV

Answer 8

Volume of distribution in central compartment

Vc = Dose / (C1 + C2)

Question 9

Css Volume - IV

Answer 9

Rate of drug entry into both compartments form the other are equal at Css

Vss = Vc * [1 + K12/K21]

• *Function of transfer rates, NOT effected by elimination changes, true volume of distribution**
• Useful when seeing is a disease or drug-drug interaction affects the body’s ability to eliminate drug or space for drug distribution

Question 10

Clearance

Answer 10

Cl = F * Dose / AUC

Same equation for oral and IV

Question 11

AUC - IV

Answer 11

2-compartment : AUC = C1/lambda1 + C2/lambda2

Continue pattern for as many compartments in model

Question 12

AUMC

Answer 12

• Area under first moment curve
• t * C = first moment, since C is multiplied by time raised to power of 1
• AUMC is calculated as t*C is intergrated from 0 to infinity

Question 13

MRT

Answer 13

• Mean Residence Time
• Average time drug resides in the body
• Only parameter that requires multiple half lives
• Useful when comparing 2 systems (health v.s. disease)

Question 14

Multiple Compartment Models: Oral

Answer 14

• Difficulties in modeling since 3 biological processes are included: absorption, distribution, and elimination
• Overall representation of equations and models are more complex and require special computers to calculate the parameters
• Visual determination of 2-compartment characterisitcs of oral medication are not always possible and need curve-fitting software to determine
• Drug usually given IV to determine if it follows the 2-compartment system

Question 15

Oral Multiple Compartment Variables

Answer 15

Xa = amount of drug in absorption compartment
Ka = absorption rate constant
All other variables are the same as IV

Question 16

Vc - Oral

Answer 16

F * Dose / AUC *k10

Question 17

Vss - Oral

Answer 17

F * Dose / AUC * lambda2

Question 18

Are transfer constants calculated the same way in oral and IV compartment models?

Answer 18

Yes, they are unaffected by absorption.

Question 19

Equations not included

Answer 19

Equations not included were too complicated to type out and should be included on the equation sheet, make sure you are familiar with them for the exam.