Estimating the time after administration
In any situation requiring the formation of an opinion, it is important to establish the known relevant facts. In this case, it will be essential to determine the likely route of ingestion from the circumstances and clinical or pathological data, the physiological state of the person and their relevant personal characteristics (weight, age and sex), and the likely minimum and maximum time boundaries. One of the most useful tests to indicate time in fatal poisonings is the measurement of gastric contents and, if possible, bowel contents. This test is easy to perform but must include the whole contents to be useful and must show a mass amount, i.e. milligrams of drug found in the contents. The presence of substantial drug relevant to the dosage form probably indicates oral consumption and, if present in the gastric contents, relatively recent ingestion, i.e. a few hours before death.
Care is needed to avoid over-interpreting these data, since coma and certain other physiological states can lead to reduced gut motility which substantially delays gastric emptying time and drug absorption from the bowel. Furthermore, most drugs are excreted into bile and may be present in measurable amounts in gastric and bowel contents even following intravenous injection. For example, morphine has biliary concentrations some 20–100-fold over those in blood. As a result, sub milligram amounts of morphine and morphine conjugates may be excreted into the bowel. Another measure to establish recency of drug use is the absence of significant amounts of the drug in urine. This is a useful test in cases of diamorphine overdose when death has occurred soon after injection (presence of morphine in blood) and little or no morphine is present in urine ( 1mg/L of total morphine). This indicates that death occurred within several minutes of injection. It is import ant to realise that the absence of the drug in urine also indicates that there was no use of this drug in the day or two prior to the most recent dose. If a dose was administered in this period, the drug will be present in urine even in a rapid death. Despite these limitations, this test can be useful in a significant number of diamorphine deaths. When a drug has a relatively rapid rate of metabolism, the relationship between time and drug or metabolite concentrations can help to indicate whether the drug was taken recently or in the more distant past. Diamorphine is rapidly metabolised to morphine via 6-acetylmorphine. Following intravenous injection, neither diamorphine nor 6-acetylmorphine can be detected in postmortem tissues if the survival time is prolonged. Thus, even if only traces of 6-acetylmorphine are detected in a postmortem sample of blood, this indicates intravenous use of diamorphine in the very recent past, or the use of massive doses. No matter how rapidly death occurs, diamorphine itself is rarely detected because of the hydrolytic action of the plasma esterases. Cannabis provides a similar example. The detection of D9-tetrahydrocannabinol in blood ( 2ng/mL) indicates very recent use of the drug (within 8 h). Further, the concentrations of 11-nor-D9-tetrahydrocannabinol-9-carboxylic acid and its glucuronide increase with time, the ratio of the acid to D9-tetrahydrocannabinol increasing to over 50 after about 3 h. This metabolite can be present in blood for several days, whereas the pharmacological effects only persist for some few hours. If acute use of cannabis is known, then pharmacokinetic modelling can be used to estimate time of ingestion.
Concentration ratios of drug: metabolite or metabolite: metabolite can provide an estimate of the time since ingestion. Unless a drug is very rapidly metabolised (as is the case with diamorphine, cocaine and cannabis), only very low blood concentrations of metabolites are present a short time after a single dose. Consequently, a relatively high drug: metabolite ratio can be expected in cases of very rapid death following acute overdose. Conversely, the presence of significant amounts of metabolite indicate sufficient time has existed for metabolism to occur.
As well as relating drug and metabolite concentrations in the same biological sample, the concentration of the drug in one tissue can be related to a concentration in another. For example, if a fatality occurs shortly after the oral ingestion of a drug, then the liver: blood concentration ratio is higher than if death had occurred after a more prolonged period. In fact, liver concentrations can be more reliable measures of toxicity than blood for compounds subject to significant postmortem redistribution, e.g. tricyclic antidepressants, dextropropoxyphene and phenothiazines. Frequently one may need to estimate a likely dose taken some hours previously to a measured drug concentration. This can be calculated if a reasonable estimate of half-life is available from the equation:
Cx=Ct e0.693DT/half-life
where Cx is the concentration required at DT hours before the measured concentration Ct. This equation only works if the blood concentration versus time curve is in the elimination part of the pharmacokinetic curve relevant to the half-life of first-order elimination, and if the half-life has not been affected by disease, injuries or saturable metabolism. It is advised that a range of likely half-life data be used to indicate a likely range of blood concentrations. This will give a much more realistic estimate than a point calculation.
For alcohol, this equation does not apply since ethanol elimination is for the most part zero order, or more accurately obeys Michaelis Menten kinetics. Michaelis–Menten kinetics is defined by the term:
where Km is a constant equal to the plasma concentration at which the rate is one-half of the maximum, R is the rate of metabolism and Vmax is the maximum rate of metabolism. In practice, the rate of elimination over most of the blood ethanol concentration (BAC) range can be regarded as 0.015 g/100 mL per h, with a common range of 0.010–0.020 g/100 mL per h. Back calculation can be made based on a linear model using the point estimate and the likely extremes. With very high-strength alcoholic beverages, absorption of ethanol is retarded and may take up to 2 hours. Some alcoholics will be able to eliminate alcohol faster than 0.020 g/100 mL per h, and in some individuals at very high BAC microsomal metabolism of alcohol may also occur; this is rarely beyond 0.025 g/100 mL per h, however.
