Pharmacokinetics
Postmortem toxicologists tend to interpret drug concentrations simply in the terms ‘What role, if any, did these substances play in the death of this person?’ While this question is important, lawyers, judges and the public frequently ask, ‘How many tablets did the person take and when did they take them?’ The non-scientist readily understands the concept of ‘dose’ (the number of tablets a person took, compared to the prescribed dose). However, the concept of ‘blood concentration’ and its relationship (or lack thereof) with time and dose is more difficult to understand. Pharmacokinetics is, in theory, a scientific tool that could bridge the link between the concentration of a drug in the blood and dosage. However, pharmacokinetics can be misapplied in postmortem cases.
Pharmacokinetics is an invaluable tool to help understand the time course of drugs in the body. In the living, it can be used to determine duration of action, inter-individual differences in peak plasma concentrations and clearance, and the likely effectiveness of different pharmaceutical formulations. However, rarely can pharmacokinetics be applied successfully to postmortem toxicology. When clinical pharmacokinetic studies are performed, the dose and time of dose are controlled, and often multiple plasma samples are collected to determine the pharmacokinetic parameters for a drug. For living persons, determination of the dose from a single plasma or blood concentration is fraught with uncertainty. The problem is even more complex for postmortem cases. The most common equation applied is:
Dose (g) = C (g/L) x body mass (kg) x VD (L/kg) (7.1)
where C is the concentration of drug in plasma or blood and VD is the volume of distribution. For postmortem cases, only the body mass of the deceased can be ascertained with certainty and in many cases even this may be inaccurate, for example where decomposition has occurred. The VD for any given drug typically varies over a range of at least 2-fold in the general population, and frequently more. Theoretically, the concentration of a drug can be determined with reason able accuracy in the blood sampled. In postmortem cases, there is always uncertainty whether the concentration of drug in the sample was the same, or similar, at the time of death. Furthermore, the use of calculations that involve VD assumes that absorption of the drug is complete and the drug is in equilibrium throughout the body. In postmortem cases this assumption may be invalid, especially when dealing with acute intoxications or overdoses. As a result, dose calculations may overestimate a dose by as much as 10-fold or more.
Forensic toxicologists have occasionally used analysis of multiple tissue samples from various organs in the body in attempt to overcome the errors inherent in the use of VD calculations. The approach requires quantitative analysis of tissue from multiple organs and sites to estimate the total body burden of a drug – that is the total amount in the body. At the very least, the major organs such as liver, lungs and brain must be analysed, in addition to skeletal muscle and adipose tissue. Masses measured at autopsy can be used to calculate the total drug in the organs sampled. However, the masses of skeletal muscle and adipose tissue can only be estimated realistically from historical data (Butler 1971; Ciba Geigy 1971), and may poorly reflect the actual tissue masses in the victim. As previously discussed, the concentration of a drug in the piece of organ or other tissue measured may or may not reflect the average for all of that organ or tissue. Another often overlooked factor is that, after chronic dosing, steady-state levels for some drugs, especially those with a large VD and long half-life, may be several-fold higher after chronic therapeutic dosing than after a single dose.
To summarise, therefore, pharmacokinetic calculations should be attempted with extreme caution, if at all, and any assumptions made should be stated clearly. In most instances, pharmacokinetic calculations using postmortem blood measurements are rarely defensible forensically.
