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Thomas Kraemer - One of the best experts on this subject based on the ideXlab platform.
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studies on the metabolism of the Fentanyl derived designer drug butyrFentanyl in human in vitro liver preparations and authentic human samples using liquid chromatography high resolution mass spectrometry lc hrms
Drug Testing and Analysis, 2017Co-Authors: Andrea E Steuer, Elena Williner, Sandra N Staeheli, Thomas KraemerAbstract:Increasing numbers of new psychoactive substances (NPS) among them Fentanyl Derivatives has been reported by the European monitoring centre for drugs and drug addiction (EMCDDA). ButyrFentanyl is a new Fentanyl Derivative whose potency ratio was found to be seven compared to morphine and 0.13 compared to Fentanyl. Several case reports on butyrFentanyl intoxications have been described. Little is known about its pharmacokinetic properties including its metabolism. However, knowledge of metabolism is essential for analytical detection in clinical and forensic toxicology. Therefore, in vitro and in vivo phase I and phase II metabolites of butyrFentanyl were elucidated combining liquid chromatography with a qTOF high resolution mass spectrometer. Human liver microsomes and recombinant cytochrome P450 enzymes (CYP) were used for in vitro assays. Authentic blood and urine samples from a fatal intoxication case were available for in vivo comparison. ButyrFentanyl was shown to undergo extensive metabolism. Six pathways could be postulated with hydroxylation and N-dealkylation being the major ones in vitro. In vivo, hydroxylation of the butanamide side chain followed by subsequent oxidation to the carboxylic acid represented the major metabolic step in the authentic case. Initial screening experiments with the most relevant CYPs indicated that mainly CYP2D6 and 3A4 were involved in the primary metabolic steps. Altered CYP2D6 and CYP3A4 status might cause a different metabolite pattern, making the inclusion of metabolites of different pathways recommendable when applying targeted screening procedures in clinical and forensic toxicology.This article is protected by copyright. All rights reserved. Language: en
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Studies on the metabolism of the Fentanyl-derived designer drug butyrFentanyl in human in vitro liver preparations and authentic human samples using liquid chromatography-high resolution mass spectrometry (LC-HRMS).
Drug Testing and Analysis, 2016Co-Authors: Andrea E Steuer, Elena Williner, Sandra N Staeheli, Thomas KraemerAbstract:Increasing numbers of new psychoactive substances (NPS) among them Fentanyl Derivatives has been reported by the European monitoring centre for drugs and drug addiction (EMCDDA). ButyrFentanyl is a new Fentanyl Derivative whose potency ratio was found to be seven compared to morphine and 0.13 compared to Fentanyl. Several case reports on butyrFentanyl intoxications have been described. Little is known about its pharmacokinetic properties including its metabolism. However, knowledge of metabolism is essential for analytical detection in clinical and forensic toxicology. Therefore, in vitro and in vivo phase I and phase II metabolites of butyrFentanyl were elucidated combining liquid chromatography with a qTOF high resolution mass spectrometer. Human liver microsomes and recombinant cytochrome P450 enzymes (CYP) were used for in vitro assays. Authentic blood and urine samples from a fatal intoxication case were available for in vivo comparison. ButyrFentanyl was shown to undergo extensive metabolism. Six pathways could be postulated with hydroxylation and N-dealkylation being the major ones in vitro. In vivo, hydroxylation of the butanamide side chain followed by subsequent oxidation to the carboxylic acid represented the major metabolic step in the authentic case. Initial screening experiments with the most relevant CYPs indicated that mainly CYP2D6 and 3A4 were involved in the primary metabolic steps. Altered CYP2D6 and CYP3A4 status might cause a different metabolite pattern, making the inclusion of metabolites of different pathways recommendable when applying targeted screening procedures in clinical and forensic toxicology. Copyright © 2016 John Wiley & Sons, Ltd.
Jerome R. Bagley - One of the best experts on this subject based on the ideXlab platform.
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Effects of a novel Fentanyl Derivative on drug discrimination and learning in rhesus monkeys.
Pharmacology Biochemistry and Behavior, 1999Co-Authors: Lisa R Gerak, Joseph M. Moerschbaecher, Jerome R. Bagley, Linda L. BrockunierAbstract:Abstract Three monkeys discriminated 1.78 mg/kg of mirfentanil while responding under a fixed-ratio 5 schedule of stimulus-shock termination. Two mirfentanil Derivatives, OHM3295 and OHM10579, substituted for mirfentanil in all subjects. However, other drugs produced variable effects among monkeys; for example, μ and κ opioid agonists and clonidine substituted for mirfentanil on some occasions in two monkeys. Cocaine, amphetamine, and ketamine did not substitute in any subject. Opioid antagonists did not attenuate the effects of mirfentanil. In monkeys responding under a repeated acquisition and performance procedure, errors increased only during the acquisition phase at doses of mirfentanil that decreased response rates. Thus, unlike Fentanyl, the discriminative stimulus effects of mirfentanil do not appear to be mediated exclusively through opioid receptors. Finally, mirfentanil does not appear to disrupt complex behavioral processes.
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The rate-decreasing effects of Fentanyl Derivatives in pigeons before, during and after chronic morphine treatment
Psychopharmacology, 1998Co-Authors: Cheryl A. Gauthier, Jerome R. Bagley, Lisa R Gerak, L. L. Brockunier, C. P. FranceAbstract:Mirfentanil is a Fentanyl Derivative with non-opioid actions, including non-opioid antinociceptive effects in rhesus monkeys. The current study examined the rate-altering effects of mirfentanil and several other compounds in pigeons to assess: 1) the opioid and non-opioid actions of acutely-administered Fentanyl Derivatives; and 2) the development of cross-tolerance between each of these compounds and morphine. Seven pigeons responded under a fixed-ratio 20 (FR20) schedule of food delivery. In untreated pigeons, Fentanyl, morphine, naltrexone, ketamine and three Fentanyl Derivatives (mirfentanil, OHM3463 and OHM3295) decreased rates of key pecking in a dose-related manner. Naltrexone (0.1–1.0 mg/kg) attenuated the effects of OHM3463 and not mirfentanil or OHM3295, suggesting non-opioid mediation of the rate-decreasing effects for the latter two Fentanyl Derivatives. Subjects were treated daily with morphine for 9 weeks, up to a dose of 100 mg/kg per day, during which time the dose-effect curves for morphine, Fentanyl and OHM3463 shifted rightward 6-, 10- and 2-fold, respectively, indicating the development of tolerance to morphine and cross-tolerance to Fentanyl and OHM3463. Dose-effect curves for ketamine, OHM3295 and mirfentanil were not shifted to the right during morphine treatment, and the dose-effect curve for naltrexone was shifted leftward 180-fold. To the extent that rate-decreasing effects are predictive of antinociceptive effects, these data suggest that some Fentanyl Derivatives might be useful therapeutics under conditions where tolerance develops to morphine-like opioids.
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Behavioral Effects and Binding Affinities of the Fentanyl Derivative OHM3507
Pharmacology Biochemistry and Behavior, 1998Co-Authors: S.c Ahn, Linda L. Brockunier, Jerome R. Bagley, Michael R. Brandt, Peter J. Winsauer, Joseph M. MoerschbaecherAbstract:Abstract Several Fentanyl Derivatives have been reported to have novel pharmacologies that might be exploited for developing alternate approaches to the treatment of pain. The purpose of the current series of studies was to evaluate OHM3507, a novel Fentanyl Derivative reported to have an unusual pharmacological profile in nonprimate species. Similar to several other Fentanyl Derivatives with clinical potential, OHM3507 had the highest affinity ( IC 50 = 10 nM ) for μ[ 3 H]D-Ala 2 ,N-Me-Phe 4 , Gly 5 -OH–labeled) receptors with 6- and 176-fold lower affinity for δ ([ 3 H]D-Pen 2 -D-Pen 5 –labeled), and κ [ 3 H]ethylketocyclazocine–labeled) receptors, respectively. In rhesus monkeys, OHM3507 shared discriminative stimulus effects with morphine, increased tail-withdrawal latencies in a warm-water procedure of antinociception, decreased ventilation in monkeys breathing normal air or 5% CO 2 , and failed to modify accuracy on acquisition and performance tasks up to doses that decreased rates of food-maintained responding. The opioid antagonists naltrexone and naltrindole antagonized the behavioral effects of OHM3507 in a manner that was consistent with μ-receptor mediation. Although OHM3507 appeared to have low efficacy opioid actions in nonprimate species, results from the current studies clearly show this compound to have strong, Fentanyl-like μ agonist actions in rhesus monkeys. These results provide another example of the sometimes poor predictability in the behavioral pharmacology of Fentanyl Derivatives among species, in this case between monkeys and rats, mice and rabbits, and demonstrates the need for evaluating new drugs under a broad range of conditions to increase the probability of identifying novel compounds that can be used to treat pain.
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ohm3597 a novel Fentanyl Derivative with morphine like behavioral effects in rhesus monkeys
Drug Development Research, 1995Co-Authors: Daniel J.j. Carr, Linda L. Brockunier, Jerome R. BagleyAbstract:OHM3597, a Fentanyl-like piperidine with a thalidomide-like moiety, was studied in rhesus monkeys for its behavioral effects and for its effects on lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-α, OHM3597 had morphine-like discriminative stimulus effects that were antagonized by naltrexone in a manner that was consistent with μ receptor mediation. OHM3597 also had antinociceptive effects, producing a maximal (20 sec) antinociceptive effect in a tail withdrawal procedure with a 50°C stimulus. This effect of OHM3597 also was antagonized by naltrexone in a dose-related manner. Behavioral effects of this Fentanyl Derivative had a rapid onset and a relatively short duration of action; discriminative stimulus effects were evident 3 min after subcutaneous (sc) administration of 0.32 mg (0.58 μM)/kg of OHM3597 and the duration of antinociceptive effects produced by 1.0 mg (1.6 μM)/kg (sc) was less than 90 min. OHM3597 also was compared to thalidomide for its effects on LPS-induced TNF-α production in peripheral blood mononuclear cells that were obtained from drug-naive rhesus monkeys. Thalidomide suppressed the production of TNF-α in a concentration-dependent manner with concentrations of 10 nM and 1 μM of thalidomide decreasing TNF-α levels to 81 and 65%, respectively, of control (saline) values. In contrast, up to a concentration of 1 μM, OHM3597 failed to suppress LPS-induced TNF-α production. These results demonstrate OHM3597 to be a potent, morphine-like opioid with a relatively short duration of action. Although OHM3597 did not alter TNF-α production, a compound with both antinociceptive and immunomodulatory effects might be available within this chemical series and could provide a unique approach to the concurrent treatment of pain and infectious disease. © 1995 Wiley-Liss, Inc.
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OHM3597: A novel Fentanyl Derivative with morphine‐like behavioral effects in rhesus monkeys
Drug Development Research, 1995Co-Authors: Daniel J.j. Carr, Linda L. Brockunier, Jerome R. BagleyAbstract:OHM3597, a Fentanyl-like piperidine with a thalidomide-like moiety, was studied in rhesus monkeys for its behavioral effects and for its effects on lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)-α, OHM3597 had morphine-like discriminative stimulus effects that were antagonized by naltrexone in a manner that was consistent with μ receptor mediation. OHM3597 also had antinociceptive effects, producing a maximal (20 sec) antinociceptive effect in a tail withdrawal procedure with a 50°C stimulus. This effect of OHM3597 also was antagonized by naltrexone in a dose-related manner. Behavioral effects of this Fentanyl Derivative had a rapid onset and a relatively short duration of action; discriminative stimulus effects were evident 3 min after subcutaneous (sc) administration of 0.32 mg (0.58 μM)/kg of OHM3597 and the duration of antinociceptive effects produced by 1.0 mg (1.6 μM)/kg (sc) was less than 90 min. OHM3597 also was compared to thalidomide for its effects on LPS-induced TNF-α production in peripheral blood mononuclear cells that were obtained from drug-naive rhesus monkeys. Thalidomide suppressed the production of TNF-α in a concentration-dependent manner with concentrations of 10 nM and 1 μM of thalidomide decreasing TNF-α levels to 81 and 65%, respectively, of control (saline) values. In contrast, up to a concentration of 1 μM, OHM3597 failed to suppress LPS-induced TNF-α production. These results demonstrate OHM3597 to be a potent, morphine-like opioid with a relatively short duration of action. Although OHM3597 did not alter TNF-α production, a compound with both antinociceptive and immunomodulatory effects might be available within this chemical series and could provide a unique approach to the concurrent treatment of pain and infectious disease. © 1995 Wiley-Liss, Inc.
Andrea E Steuer - One of the best experts on this subject based on the ideXlab platform.
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studies on the metabolism of the Fentanyl derived designer drug butyrFentanyl in human in vitro liver preparations and authentic human samples using liquid chromatography high resolution mass spectrometry lc hrms
Drug Testing and Analysis, 2017Co-Authors: Andrea E Steuer, Elena Williner, Sandra N Staeheli, Thomas KraemerAbstract:Increasing numbers of new psychoactive substances (NPS) among them Fentanyl Derivatives has been reported by the European monitoring centre for drugs and drug addiction (EMCDDA). ButyrFentanyl is a new Fentanyl Derivative whose potency ratio was found to be seven compared to morphine and 0.13 compared to Fentanyl. Several case reports on butyrFentanyl intoxications have been described. Little is known about its pharmacokinetic properties including its metabolism. However, knowledge of metabolism is essential for analytical detection in clinical and forensic toxicology. Therefore, in vitro and in vivo phase I and phase II metabolites of butyrFentanyl were elucidated combining liquid chromatography with a qTOF high resolution mass spectrometer. Human liver microsomes and recombinant cytochrome P450 enzymes (CYP) were used for in vitro assays. Authentic blood and urine samples from a fatal intoxication case were available for in vivo comparison. ButyrFentanyl was shown to undergo extensive metabolism. Six pathways could be postulated with hydroxylation and N-dealkylation being the major ones in vitro. In vivo, hydroxylation of the butanamide side chain followed by subsequent oxidation to the carboxylic acid represented the major metabolic step in the authentic case. Initial screening experiments with the most relevant CYPs indicated that mainly CYP2D6 and 3A4 were involved in the primary metabolic steps. Altered CYP2D6 and CYP3A4 status might cause a different metabolite pattern, making the inclusion of metabolites of different pathways recommendable when applying targeted screening procedures in clinical and forensic toxicology.This article is protected by copyright. All rights reserved. Language: en
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Studies on the metabolism of the Fentanyl-derived designer drug butyrFentanyl in human in vitro liver preparations and authentic human samples using liquid chromatography-high resolution mass spectrometry (LC-HRMS).
Drug Testing and Analysis, 2016Co-Authors: Andrea E Steuer, Elena Williner, Sandra N Staeheli, Thomas KraemerAbstract:Increasing numbers of new psychoactive substances (NPS) among them Fentanyl Derivatives has been reported by the European monitoring centre for drugs and drug addiction (EMCDDA). ButyrFentanyl is a new Fentanyl Derivative whose potency ratio was found to be seven compared to morphine and 0.13 compared to Fentanyl. Several case reports on butyrFentanyl intoxications have been described. Little is known about its pharmacokinetic properties including its metabolism. However, knowledge of metabolism is essential for analytical detection in clinical and forensic toxicology. Therefore, in vitro and in vivo phase I and phase II metabolites of butyrFentanyl were elucidated combining liquid chromatography with a qTOF high resolution mass spectrometer. Human liver microsomes and recombinant cytochrome P450 enzymes (CYP) were used for in vitro assays. Authentic blood and urine samples from a fatal intoxication case were available for in vivo comparison. ButyrFentanyl was shown to undergo extensive metabolism. Six pathways could be postulated with hydroxylation and N-dealkylation being the major ones in vitro. In vivo, hydroxylation of the butanamide side chain followed by subsequent oxidation to the carboxylic acid represented the major metabolic step in the authentic case. Initial screening experiments with the most relevant CYPs indicated that mainly CYP2D6 and 3A4 were involved in the primary metabolic steps. Altered CYP2D6 and CYP3A4 status might cause a different metabolite pattern, making the inclusion of metabolites of different pathways recommendable when applying targeted screening procedures in clinical and forensic toxicology. Copyright © 2016 John Wiley & Sons, Ltd.
J. H. Woods - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological profile of a potent, efficacious Fentanyl Derivative in rhesus monkeys
Psychopharmacology, 1992Co-Authors: C. P. France, G. Winger, M. R. Seggel, K. C. Rice, J. H. WoodsAbstract:The recent synthesis of Fentanyl Derivatives, some of which appear to have novel profiles of pharmacological effects, has provided compelling evidence that μ opioid efficacy might be altered systematically by modifications in the parent compound Fentanyl. In the present study a new 4-(heteroanilido)-piperidine, compound 28, was studied for its effects in rhesus monkeys. In self-administration studies compound 28 maintained rates of lever pressing similar to those maintained by alfentanil; the reinforcing effects of compound 28 were attenuated by the opioid antagonist quadazocine. In drug discrimination studies compound 28 did not substitute for the κ agonist ethylketocyclazocine and did substitute for the μ agonist alfentanil. In morphine-treated subjects discriminating between saline and naltrexone, compound 28 did not substitute for naltrexone; however, in morphine-abstinent subjects compound 28 reversed naltrexone lever responding. Moreover, this discriminative stimulus effect in morphine-abstinent subjects was antagonized by naltrexone and by quadazocine in a manner consistent with μ receptor mediation. Compound 28 also was an effective analgesic in a warm-water, tail-withdrawal procedure and it decreased markedly respiratory function. The analgesic effects as well as the respiratory depressant effects of compound 28 were antagonized by quadazocine. Together, these results show compound 28 to be a potent, efficacious μ agonist of similar potency to alfentanil. Large differences in apparent efficacy at μ receptors between compound 28 and another compound in this series (mirfentanil), clearly demonstrate that, within this chemical family, small chemical changes can confer significant differences in pharmacologic effect.
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Mirfentanil: pharmacological profile of a novel Fentanyl Derivative with opioid and nonopioid effects.
The Journal of pharmacology and experimental therapeutics, 1991Co-Authors: G. Winger, M. R. Seggel, K. C. Rice, F Medzihradsky, J. H. WoodsAbstract:Mirfentanil [N-(2-pyrazinyl)-N-(1-phenethyl-4-piperidinyl)-2-furamide] was studied for its binding affinity in isolated neuronal membranes, and for its effects in vivo. In binding to opioid receptors in monkey brain membranes, mirfentanil was much more selective for mu sites (7.99 nM) than for either kappa (1428 nM) or delta (480 nM) sites as measured by displacement of [3H]DAMGO. [3H]U-69.593 or [3H]DPDPE, respectively. In morphine-treated pigeons discriminating among naltrexone, saline and morphine, mirfentanil failed to substitute for either training drug; in morphine-abstinent pigeons, mirfentanil reversed responding on the naltrexone key (i.e., reversed withdrawal). In morphine-treated monkeys discriminating between saline and naltrexone, mirfentanil substituted completely for naltrexone, and this effect was attenuated by an acute injection of morphine; mirfentanil also attenuated the withdrawal-reversing effects of alfentanil in morphine-abstinent monkeys. Administered i.v., mirfentanil maintained rates of self-administration responding only slightly below rates maintained by alfentanil, and this effect of mirfentanil was antagonized by quadazocine. Small doses of mirfentanil (0.032-0.32 mg/kg) antagonized the analgesic effects of alfentanil; larger doses of mirfentanil both antagonized the analgesic effects of alfentanil and produced analgesic effects when administered alone. The analgesic effects of mirfentanil were not attenuated by large doses of opioid antagonists. Mirfentanil had modest respiratory depressant effects that were not altered by quadazocine; however, mirfentanil antagonized the respiratory depressant effects of large doses of alfentanil. Both in vivo and in vitro, mirfentanil appears to have selectivity for opioid mu receptors. Moreover, at doses larger than those which exert opioid effects, mirfentanil has nonopioid analgesic effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Elena Williner - One of the best experts on this subject based on the ideXlab platform.
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studies on the metabolism of the Fentanyl derived designer drug butyrFentanyl in human in vitro liver preparations and authentic human samples using liquid chromatography high resolution mass spectrometry lc hrms
Drug Testing and Analysis, 2017Co-Authors: Andrea E Steuer, Elena Williner, Sandra N Staeheli, Thomas KraemerAbstract:Increasing numbers of new psychoactive substances (NPS) among them Fentanyl Derivatives has been reported by the European monitoring centre for drugs and drug addiction (EMCDDA). ButyrFentanyl is a new Fentanyl Derivative whose potency ratio was found to be seven compared to morphine and 0.13 compared to Fentanyl. Several case reports on butyrFentanyl intoxications have been described. Little is known about its pharmacokinetic properties including its metabolism. However, knowledge of metabolism is essential for analytical detection in clinical and forensic toxicology. Therefore, in vitro and in vivo phase I and phase II metabolites of butyrFentanyl were elucidated combining liquid chromatography with a qTOF high resolution mass spectrometer. Human liver microsomes and recombinant cytochrome P450 enzymes (CYP) were used for in vitro assays. Authentic blood and urine samples from a fatal intoxication case were available for in vivo comparison. ButyrFentanyl was shown to undergo extensive metabolism. Six pathways could be postulated with hydroxylation and N-dealkylation being the major ones in vitro. In vivo, hydroxylation of the butanamide side chain followed by subsequent oxidation to the carboxylic acid represented the major metabolic step in the authentic case. Initial screening experiments with the most relevant CYPs indicated that mainly CYP2D6 and 3A4 were involved in the primary metabolic steps. Altered CYP2D6 and CYP3A4 status might cause a different metabolite pattern, making the inclusion of metabolites of different pathways recommendable when applying targeted screening procedures in clinical and forensic toxicology.This article is protected by copyright. All rights reserved. Language: en
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Studies on the metabolism of the Fentanyl-derived designer drug butyrFentanyl in human in vitro liver preparations and authentic human samples using liquid chromatography-high resolution mass spectrometry (LC-HRMS).
Drug Testing and Analysis, 2016Co-Authors: Andrea E Steuer, Elena Williner, Sandra N Staeheli, Thomas KraemerAbstract:Increasing numbers of new psychoactive substances (NPS) among them Fentanyl Derivatives has been reported by the European monitoring centre for drugs and drug addiction (EMCDDA). ButyrFentanyl is a new Fentanyl Derivative whose potency ratio was found to be seven compared to morphine and 0.13 compared to Fentanyl. Several case reports on butyrFentanyl intoxications have been described. Little is known about its pharmacokinetic properties including its metabolism. However, knowledge of metabolism is essential for analytical detection in clinical and forensic toxicology. Therefore, in vitro and in vivo phase I and phase II metabolites of butyrFentanyl were elucidated combining liquid chromatography with a qTOF high resolution mass spectrometer. Human liver microsomes and recombinant cytochrome P450 enzymes (CYP) were used for in vitro assays. Authentic blood and urine samples from a fatal intoxication case were available for in vivo comparison. ButyrFentanyl was shown to undergo extensive metabolism. Six pathways could be postulated with hydroxylation and N-dealkylation being the major ones in vitro. In vivo, hydroxylation of the butanamide side chain followed by subsequent oxidation to the carboxylic acid represented the major metabolic step in the authentic case. Initial screening experiments with the most relevant CYPs indicated that mainly CYP2D6 and 3A4 were involved in the primary metabolic steps. Altered CYP2D6 and CYP3A4 status might cause a different metabolite pattern, making the inclusion of metabolites of different pathways recommendable when applying targeted screening procedures in clinical and forensic toxicology. Copyright © 2016 John Wiley & Sons, Ltd.