Ethanol has complex pharmacokinetics (PK; Holford 1987) and pharmacodynamics
(PD; Holford 1997).
Pharmacokinetics
Ethanol PK is complex because of capacity limited
elimination (aka Michaelis-Menten or saturable kinetics). This is associated with
marked absorption rate dependent bioavailability.
Pharmacodynamics
Ethanol PD is
complex because of the rapid development of tolerance and delays in
effect which
may differ depending on the biomarker.
Exploring ethanol PKPD with simulation
A
simulation of ethanol PKPD is part of the MKMODEL program (Holford 1994). MKMODEL
is a DOS based application written in QuickBasic. Development of MKMODEL has stopped
because of its obsolete software development origins. The PKPD simulation part of
MKMODEL can be downloaded. Please check the readme.txt file for installation and
usage.
A new project has been started that will explore alternative tools for simulation
of ethanol PKPD.
Evaluation of drinking guidelines
Simulation will be used to
evaluate public web based guidelines which advise on the number of standard ethanol
drinks which are likely to keep blood ethanol concentrations below the legal driving
limit and how to calculate blood
alcohol concentration.
Ordinary differential
equations and java
The solution of ordinary differential
equations (ODEs) is a necessary part of solving non-linear pharmacokinetic models
such as those needed for ethanol PK. Java is being explored as a target language
to develop web based simulations of ethanol PKPD.
Drink
me! Excel simulation of Ethanol PK
Excel macros must be enabled to run the clinical pharmacologist simulation
model.
The idea for the DrinkMe worksheet came from an anonymous workbook developed
by a financial analyst. The financial analyst model assumes the dose is instantaneously
and completely absorbed one hour after the nominal time of the drink. It is then
eliminated by an approximate first-order process. The Excel workbook (drink plan.xls)
on which this worksheet is based has been found at Beer Beer Beer and Brisbane.
The clinical pharmacologist model is described in more detail on the Science worksheet.
The graph on the DrinkMe worksheet compares the financial analyst model (calculated
on the DrinkMe Worksheet using Excel formulae) with the well stirred mixed-order
elimination model (calculated on the Science worksheet by solving a set of simultaneous
differential equations).
The tactical chunder is implemented as an immediate loss
from the gut. The ethanol amount lost is constrained not to be more than the amount
remaining to be absorbed.
The clinical pharmacologist pharmacokinetic model is based
on first-order absorption with no lagtime and elimination by a combination of mixed
order (MO) and first order (FO) pathways. A simple MO model assumes ethanol is absorbed
into a single distribution and elimination volume. The more complex WS model assumes
ethanol undergoes absorption rate dependent first pass metabolism in a well stirred
liver compartment. The WS model depends on portal liver blood flow (Q). The instantaneous
bioavailability (Fws) assumes complete absorption from the gut into the portal vein.
The solutions to the two models for the mixed order pathway are shown on the Science
worksheet.
The model is defined using a system of differential equations and solved
using a variable step size Runge-Kutta 4/5 Order algorithm (Fehlberg 1969). The
code is based on Fortran (Forsythe, Malcolm & Moler 1977) adapted for QuickBasic
to provide a DE solver for MKMODEL (Holford 1994). The QuickBasic code was then
ported to Visual Basic for Excel simulation.
- Fehlberg E. Low-order classical Runge-Kutta
formulas with stepsize control and their application to some heat transfer problems.
NASA Technical Report 1969;R-315
- Forsythe GE, Malcolm MA, Moler CB. Computer
methods for mathematical computations. Englewood Cliffs: Prentice-Hall,Inc; 1977
- Holford
NHG. MKMODEL, a quantitative modeling system for pharmacologists. In. 5 ed. Cambridge,
MA: Biosoft; 1994
- Holford NHG. Clinical pharmacokinetics of ethanol. Clinical Pharmacokinetics
1987;13:273-292
- Holford NHG. Complex PK/PD models - an alcoholic experience. International
Journal of Clinical Pharmacology and Therapeutics 1997;35(10):465-468
