Professor Nick Holford
Department of Pharmacology & Clinical Pharmacology, FMHS, University of Auckland Professor Nick Holford
Department of Pharmacology & Clinical Pharmacology, FMHS, University of Auckland

Ethanol pharmacokinetics and pharmacodynamics

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.

  1. 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
  2. Forsythe GE, Malcolm MA, Moler CB. Computer methods for mathematical computations. Englewood Cliffs: Prentice-Hall,Inc; 1977
  3. Holford NHG. MKMODEL, a quantitative modeling system for pharmacologists. In. 5 ed. Cambridge, MA: Biosoft; 1994
  4. Holford NHG. Clinical pharmacokinetics of ethanol. Clinical Pharmacokinetics 1987;13:273-292
  5. Holford NHG. Complex PK/PD models - an alcoholic experience. International Journal of Clinical Pharmacology and Therapeutics 1997;35(10):465-468