**3.1 Techniques**

*Forensic Analysis - Scientific and Medical Techniques and Evidence under the Microscope*

UM ≥3 0 0

IM 1 2/1 1/ 1 PM 0 0 2 Examples \*1 \*9, \*10, \*17(Z) \*3, \*4, \*5, \*6, \*14 *UM, ultra-rapid metabolizer; EM, extensive metabolizer; IM, intermediate metabolizer; PM, poor metabolizer.*

**Defective functioning (decreased, reduced)**

1 1 0

2 0 0

**Nonfunctioning (dysfunction-inactive)**

**Phenotype Genotype (allele) Fully functioning**

than IMs who may experience insufficient relief. UMs are being more likely to experi-

Apart from M1, there are two additional primary TR metabolites, M2 and M5. M2 is an inactive metabolite which its formation is mediated by presence of two enzymes (CYP2B6 and CYP3A4), while M5 has some opioid effects and its metabolic route is less assured. However, all three enzymes (CYP2D6, CYP2B6, and

The CYP2B6 gene is highly polymorphic as well as CYP2D6, but the relevance of CYP2B6 polymorphisms in TR has been less studied. Many CYP3A4 polymorphisms have been identified, although it is not well associated with the phenotypical variability. The CYP3A4\*22 allele is associated with reduction of the enzymatic activity. Recent study tried to explain if the interindividual differences in enantioselective metabolic profiles could be explained by CYP2D6, CYP2B6, and/or CYP3A4 genotype. This item hypothesized that interindividual differences are better explained by the combined genotype of all three enzymes involved in the metabolism of the

Rudaz et al. showed that enantiomer ratios of all four compounds in urine changed over time in one individual administered 100 mg TR [41]. The largest increase in enantiomer ratio was observed for M2 in CYP2D6 EM and IM, rising from about two to almost seven during 24 h following drug intake. Homozygosity of CYP2B6\*5 and \*6 indicated a reduced enzyme function, although further studies are required to confirm it. The significance of CYP2B6 polymorphisms in TR pharmacokinetics has not been carefully investigated. The same study concluded that consideration for the time is important when you assess enantiomer ratios as it might possibly be used to distinguish a recent TR intake from a

Of additional relevance is the significant interethnic differences in CYP2D6 allele frequencies demonstrated across many countries [9]. For example, the CYP2D6\*1 seems to be the most prevalent in studied groups from Egyptians. In contrast, CYP2D6\*4, CYP2D6\*10 and CYP2D6\*DUP showed minor occurrence [42].

Chronic treatment with TR induced hepatotoxicity in all patients with duplicated or normal function (CYP2D6\*DUP or \*1) allele in UMs and EMs displayed higher blood levels of M1, but in none of the patients with impaired or reduced

ence adverse effects from TR because of the more rapid release of M1 [9].

CYP3A4) are involved in TR metabolism (**Figure 1**) [10].

drug, rather than by CYP2D6 itself [10].

*CYP2D6 phenotypes in relation to their genotypes.*

**166**

past one [10].

EM

**Table 1.**

EM1s (heterozygous wild-type)

EM2s (homozygous wild-type)

functioning allele \*4 or \*10 [42].

Toxicological analysis of TR is based on chemical spot tests, immunoassays, mass spectrometry, and chromatography.

