Abstract
The ongoing progress in analytical and life sciences is opening up new perspectives in post-modern medico-legal and forensic toxicology. In times of personalized medicine, the interpretation of analytical results in clinical and forensic cases should also be based on genetic aspects, pharmacogenomics in particular. Pharmacologic and toxic effects of drugs or poisons may be influenced by the genotype and phenotype of an individual, but also by the isoenzymes involved in their metabolism and membrane transport. Further individual factors such as body mass, age, sex, kidney and liver function, and drug-drug (food-drug) interactions may have an impact. Detailed knowledge of all these factors is a prerequisite for evidence-based case interpretation. In this chapter, the current knowledge of possible risks in variations of the effects of relevant therapeutic drugs, herbal drugs, and drugs of abuse will be presented. A critical discussion of the impact on the interpretation of analytical results in clinical and forensic toxicology will follow.
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1 Introduction
In times of ante-modern forensic toxicology (FT), drug concentrations were determined, for example, by spectrophotometry after thin-layer chromatographic separation and elution of the scraped spots following internal approaches. In modern FT, the blood concentrations are determined using the latest high-end mass spectrometry equipment in high resolution [1, 2] following all international guidelines for method validation and internal and external quality control [3] in an accredited laboratory. However, this analytically determined “true blood level” was/is often interpreted toxicologically by simply comparing it with a published reference list, e.g. by Schulz et al. [4]. Such lists are mainly based on data coming from controlled clinical trials of pharmaceutical companies or single case reports. Of course, this procedure is too simple for evidence-based case interpretation in times of P5 medicine and justice. While the pharmacokinetic variability within such trials is up to ten times, the variability among the real population may range up to 100 times [5]. Case reports are often well documented only for the medical or for the analytical part [6].
In (post-)modern toxicology, various effects influencing the individual drug/poison response have to be considered, such as age, gender, body-mass index, drug-drug or drug-food interactions, lifestyle and nutrition, the microbiome, and particularly the genome and epigenome [7, 8]. All effects may, for example, increase or decrease the bioavailability and plasma elimination half-life of a drug. Pharmacogenomics (PGx) plays a major role in the relationship of P5 medicine and justice [9]. In contrast to pharmacogenetics describing only the genetic variations, PGx describes multifactorial variations of drug responses caused by variable gene expression (polymorphisms), influence of drugs on genes (epigenetics), and time-dependent changes of gene expression [10]. These genetic and post-translationally acquired variations then describe the phenotype.
PGx is nowadays well established in P5 medicine, such as in oncology, transplantation, and psychiatry with the goal to find the right dose of the right drug for the right indication for the right patient at the right time [7]. Sim and Ingelman-Sundberg [11] discussed important pharmacogenomic biomarkers influencing treatment response and/or incidence for adverse drug reactions. However, the prerequisite is that the drugs are characterized during drug development concerning the influence of polymorphically expressed target proteins (receptors, ion channels, or enzymes) and proteins involved in drug transport or metabolism.
As the new psychoactive substances (NPS) are neither tested for preclinical nor clinical pharmacology and toxicology before distribution and consumption, such data have to be elucidated by, for example, academic institutions. The author’s group, for example, has studied metabolism intensively, including the kinetics of the involved (iso)enzymes [12,13,14,15,16,17,18,19,20], the cytochrome P450 (CYP) inhibition potential of NPS [21, 22], and the possible interaction with drug transporters [23]. In pharmacokinetics, various drug transporters are involved in absorption, distribution, and elimination [24, 25]. For elucidating possible impact on drug response, PGx variations or interactions have to be tested for. Meyer et al. [23] described that the investigated NPS were no substrates of the major efflux transporter P-glycoprotein (P-gp), but some were potent inhibitors. Thus, PGx variations or interactions will have no impact on the effect of these NPS, but they can produce interaction with substrates of P-gp. For example, loperamide and domperidone, both effluxed by P-gp at the blood-brain barrier, are discussed to act centrally by coadministration with P-gp inhibitors such as verapamil or quinidine.
For personalized case interpretation, Wong et al. [9] discussed various advantages and disadvantages of PGx as an adjunct biomarker in personalized justice. It is advantageous that the DNA is stable in postmortem settings and may provide a personalized approach for assessing the relation of drug response with the postmortem drug concentrations. However, there are only limited postmortem reference data available in contrast to clinical medicine. As already discussed, the legal interpretation is challenging as many posttranslational modifications have to be considered as well as interactions with inhibitors or inducers of drug metabolizing or transporting proteins.
In the following, published examples for the impact of PGx and/or interactions on real case interpretation will be discussed.
2 Evidence-Based Case Interpretation
2.1 Missing Drug Effect Caused by PGx Variations and/or Interactions
2.1.1 Tramadol in Personalized Pain Management
Tramadol is an enantioselectively metabolized by the polymorphically expressed CYP 2D6 to the more potent opioid receptor agonist O-demethyl tramadol. In the context of personalized therapy in pain management, Stamer et al. [26] could show that a patient with a CYP 2D6 poor metabolizer genotype formed the lowest blood concentrations of the active metabolite, while the ultra-rapid metabolizers formed the highest. They could confirm the clinical response correspondingly. In a further study, they gave a CYP 2D6 inhibitor to the ultra-rapid metabolizers and, as expected, they could be transferred to functional poor metabolizers with low blood concentration of the acting metabolite. Again, the blood levels correlated with the clinical outcome. This example demonstrates that the case interpretation would not be correct when the blood levels of the parent drug would have been correlated with published data.
2.1.2 Missing Pain Treatment Under Oxycodone
Lee et al. [27] described the case of a patient under pain treatment with oxycodone, but without analgesic effects. The anesthetist wanted to monitor his adherence by urine drug testing for oxycodone. The test, performed with an assay focused on the parent drug only, was negative. After intake under supervision and still no response, they thought of possible PGx variations or interactions. Oxycodone is also a prodrug bioactivated by CYP 2D6. The patient was genotyped as CYP 2D6 poor metabolizer explaining the missing analgesic effects, but what was the reason for the negative urine test? They found that the patient was under treatment of the tuberculostatic rifampicin for years. Thus, the patient showed a significant induction of CYP 3A4, the enzyme responsible for the major metabolizing step leading to the pharmacologically inactive N-dealkyl metabolite. This example shows the above-mentioned complexity of evidence-based case interpretation. Incomplete drug testing with missing targets may lead to misinterpretation of the adherence test, drug-drug interaction as well as genetic variations in forming the acting metabolite, making a simple case interpretation impossible.
2.2 Poisoning Caused by PGx Variations and/or Interactions
2.2.1 Narcotic Syndrome After Codeine Administration
Gasche et al. [28] described a narcotic syndrome of a patient under therapeutic doses of codeine. Genotyping revealed that the patient was a CYP 2D6 ultra-rapid metabolizer forming a higher rate of the acting O-demethyl metabolite morphine. He was additionally under co-administration of the potent CYP 3A4 inhibitors clarithromycin and voriconazole. Thus, the main metabolizing step, namely the formation of the inactive N-demethyl metabolite, was blocked, resulting in even more morphine production. Finally, the patient suffered from an acute renal failure resulting in a limited elimination of the morphine-6-glucuronide, which can pass the blood-brain barrier and act as potent opioid. Again, this case shows that all aspects of PGx, interactions, and the body functions have to be considered when interpreting analytical results.
2.2.2 Fatal Poisoning After Breast Feeding of the Mother Under Codeine Treatment
Madadi et al. described a fatal morphine poisoning of a newborn after breast feeding of the mother under codeine treatment. The mother was a CYP2D6 ultra-rapid metabolizer forming high concentrations of morphine. This example shows that PGx and interactions must also be considered in such cases when the mother may be accused of having killed the newborn by application of morphine.
3 Conclusions
In post-modern toxicology, it is a must—at least in any unclear cases—to consider pharmacogenomic variations and interactions in interpretation of analytical results. However, it is essential that the above-mentioned limitations are considered of genotyping detecting only the genetic risks. Antemortem, phenotyping [29] is preferred to detect genetic and acquired posttranscriptional variations. The future will show whether in postmortem cases, direct determination of the modified proteins (metabolizing enzymes, transporters etc.) can be determined by high-resolution mass spectrometry. On the other hand, over-interpretation of all above-mentioned aspects by untrained experts must be excluded.
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Maurer, H.H. (2017). Post-modern Medicolegal and Forensic Toxicology. In: Ferrara, S. (eds) P5 Medicine and Justice. Springer, Cham. https://doi.org/10.1007/978-3-319-67092-8_29
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