Chapter 17 - Page 2 - Java 2

Linear Plot of Cp versus Time after a Single IV Bolus Dose Administration One Compartment Model - Liver Metabolism Models

Hepatic clearance can be calculated from three parameters according the well stirred model and the parallel tube model. These parameters are intrinsic, unbound clearance (CL_int), fraction unbound (fu) and hepatic blood flow (Q_H). The equations for these two models are different but they contain the same three parameters.

Equation 17.2.1 Hepatic Clearance according to the Well Stirred Model

Equation 17.2.2 Hepatic Clearance according to the Parallel Tube Model

Table of Parameter Values that might be useful with this simulation

Parameter Value Comment

Dose 100 mg ± Linear system in this example

Volume of Distribution
V Range 7 - 200+ L

Excretion Rate Constant
ke Range 0 - 5+ hr^-1 Non hepatic excretion/elimination

Unbound Intrinsic Clearance
CL_{int, ub} 0 - 1500+ L/hr Shargel and Yu, 3rd, 1993

Hepatic Blood Flow
Q_H 90 L/hr
Range 60-120 L/hr 70 Kg adult, Shargel and Yu, 3rd, 1993

Fraction unbound, in blood
fu, b Range 0 - 1

Equations used in this simple pharmacokinetic model.

Equation 17.2.3 Elimination Rate Constant as a function of CL_H, V and ke

Equation 17.2.4 Concencentration versus Time after a single IV Bolus Dose

Equation 17.2.5 Extraction Ratio calculated from CL_H and Q_H

Explore flow limited drug behavior by setting CL_int somewhat larger (> 200 L/hr) than the hepatic blood flow rate. Change Q_H, fu and CL_int to see which parameters have the greatest influence of half-life and AUC. Capacity limited drug behavior can be explored by setting CL_int to a lower value (< 40 L/hr). Explore the effect of V on drug half-life.

Explore the equation by changing the parameter(s). Add additional lines with different parameter values using the Add Line button.

References

Burton, M.E., Shaw, L.M., Schentag, J.J., and Evans, W.E. (editors) 2006. Applied Pharmacokinetics & Pharmacodynamics, Principles of Therapeutic Drug Monitoring, Lippincott Williams & Wilkins, p133
Kwon, Y. 2001 Handbook of Essential Pharmacokinetics, Pharmacodynamics, and Drug Metabolism for Industrial Scientists, Kluwer Academic/Plenum Publishers, pp 90-95
Shargel, L., Wu-Pong, S. and Yu, A.B.C. 2005 Applied Biopharmaceutics and Pharmacokinetics, 5th ed., McGraw-Hill, pp 342-343

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Parameter	Value	Comment
Dose	100 mg ±	Linear system in this example
Volume of Distribution V	Range 7 - 200+ L
Excretion Rate Constant ke	Range 0 - 5+ hr^-1	Non hepatic excretion/elimination
Unbound Intrinsic Clearance CL_{int, ub}	0 - 1500+ L/hr	Shargel and Yu, 3rd, 1993
Hepatic Blood Flow Q_H	90 L/hr Range 60-120 L/hr	70 Kg adult, Shargel and Yu, 3rd, 1993
Fraction unbound, in blood fu, b	Range 0 - 1