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1.
J Anal Toxicol ; 48(5): 299-313, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38491987

RESUMO

New psychoactive substances (NPS), like pyrrolidinophenones, are still very present on the illegal drug market. The presented study reports on two members of this substance group, α-pyrrolidinohexanophenone (α-PHP) and α-pyrrolidinoisohexanophenone (α-PiHP), which occurred in forensic routine cases in the last 6 years. α-PHP could be detected predominantly by a validated liquid chromatography-tandem mass spectrometry (LC-MS-MS) method in 33 authentic human plasma samples and α-PiHP in 8. α-PHP concentrations ranged from ca. 0.75 to 128 µg/L (mean: 23.2, median: 16.3) and α-PiHP concentrations from 7.33 to 118 µg/L (mean: 44.7, median: 33.7, quantified via α-PHP). Individuals were predominantly male and middle aged. As different studies have shown, some pyrrolidinophenones are able to cause aggressive behavior. Therefore, we set out to investigate the relation of α-PHP and α-PiHP plasma concentrations and the behavior of the consumers, reported by police and medical experts. Part of the subjects showed aggressive behavior, including agitation and restlessness. Lethargic and unremarkable behavior might be explained by co-consumption of other drugs, such as opiates/opioids, benzodiazepines, pregabalin or alcohol as well as by drug tolerance and subacute effects of stimulants. Multi-drug use could be detected in all cases; also stimulating substances and multiple different pyrrolidinophenones were determined. Nevertheless, users of α-PHP and α-PiHP showed a tendency to act aggressively, possibly triggered by a high selectivity for dopamine transporter inhibition. In accordance, committed offenses were often violent crimes. This might be considered in terms of toxicological assessment of criminal responsibility and driving ability.


Assuntos
Pirrolidinas , Detecção do Abuso de Substâncias , Espectrometria de Massas em Tandem , Humanos , Detecção do Abuso de Substâncias/métodos , Pirrolidinas/sangue , Masculino , Cromatografia Líquida , Feminino , Drogas Ilícitas/sangue , Pirrolidinonas/sangue , Adulto , Toxicologia Forense/métodos , Psicotrópicos/sangue , Pessoa de Meia-Idade
2.
Forensic Sci Int ; 321: 110721, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33640778

RESUMO

Alpha-Pyrrolidinopentiothiophenone (α-PVT) belongs to the drug class of pyrrolidinophenones, a subgroup of synthetic cathinones, which are among the most prevalent new psychoactive substances. The study describes a series of 44 authentic forensic cases with analytical confirmed intake of α-PVT. Plasma concentrations, determined by a validated LC-MS/MS method, ranged from ca. 0.9 to 306 µg/L (median 35.6; mean 66.6 µg/L). Comprehensive toxicological analysis proved excessive co-consumption in almost all cases, including other pyrovalerones and classic stimulants as well as central depressant drugs such as opiates/opioids, benzodiazepines, pregabalin and/or ethanol. Subjects were aged between 26 and 54 years (median 35 years, mean 36 years) and appeared to be mainly experienced intravenous drug consumers. A high incidence of aberrant behavior in terms of aggressive, combative behavior and psychotic changes could be observed, as also reflected in accused offences, which frequently presented violent crimes. In consideration of several confounding factors, the study suggests a relationship between frequency of such impairment and plasma concentrations of α-PVT, but individual cases without signs of behavioral changes and high plasma concentrations also occurred, which might be explained by developed tolerance and/or individual vulnerably for the psychotic effects of pyrovalerones.


Assuntos
Psicotrópicos/sangue , Pirrolidinas/sangue , Tiofenos/sangue , Adulto , Agressão , Cromatografia Líquida , Feminino , Toxicologia Forense , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Pessoa de Meia-Idade , Psicoses Induzidas por Substâncias , Psicotrópicos/efeitos adversos , Pirrolidinas/efeitos adversos , Detecção do Abuso de Substâncias , Espectrometria de Massas em Tandem , Tiofenos/efeitos adversos
3.
Drug Test Anal ; 12(10): 1470-1476, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32652866

RESUMO

Driving under the influence of drugs (DUID) is a serious global problem and poses a public health risk. With new psychoactive substances (NPS) entering the illicit drug market several years ago, a significant number of highly potent and harmful drugs have become easily available and the use of these substances may impair a person's ability to drive a vehicle safely. Since NPS are not usually covered in routine toxicological analyses used in DUID investigations, only little is known about their prevalence. To gather more information on the prevalence of NPS in cases of impaired driving, a retrospective study was conducted to determine the prevalence of these drugs in blood samples of DUID suspects in southern Germany. A total of 837 blood samples, which were collected in the German federal states Baden-Württemberg and Bavaria in 2017 and 2018, were reanalyzed for designer stimulants and synthetic cannabinoids by liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS). For the analysis of synthetic cannabinoids, a more sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening method was additionally used. A total of 14 cases (1.6%) tested positive for NPS. Designer stimulants were detected in two cases (0.2%) and synthetic cannabinoids were found in 12 cases (1.4%). The rather low prevalence rate of 1.6% estimated in this study suggests that driving under the influence of NPS does not play a large role in southern Germany. Nonetheless, in all cases in which the psychophysical impairment cannot be explained by routine toxicological findings, a screening for NPS should additionally be performed.


Assuntos
Dirigir sob a Influência , Drogas Ilícitas/sangue , Psicotrópicos/sangue , Detecção do Abuso de Substâncias , Adulto , Alemanha , Humanos , Estudos Retrospectivos , Adulto Jovem
4.
Forensic Sci Int ; 283: 72-84, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29275216

RESUMO

The new psychoactive substance 3,4-methylenedioxypyrovalerone (MDPV) belongs to the group of synthetic cathinones and is purchased mainly as "research chemical" or "bath salt" on the illegal drug market, also in South Bavaria. MDPV was detected in blood and urine samples from 2010 on in 50 authentic routine cases in a forensic setting. Plasma concentrations in 46 cases with available blood specimens ranged from approximately 1.0 to 301µg/L (median 23.7; mean 47.9µg/L), detected by a fully validated LC-MS/MS method. Subjects aged between 16 and 54 years (median 36; mean 35 years) and reflected experienced chronic drug users. Accused offences were mainly violent crimes such as bodily harm, robberies, homicides and acts of resistance. A lot of subjects showed highly aggressive and violent behavior with endangerment of self and others and/or psychotic symptoms as confusion, hallucinations or paranoia. The risk for such behavior rises with MDPV plasma concentrations above as low as 30µg/L, whereby a time interval of 1.5h on average between incident and/or observation of impairment and blood sampling has to be taken into account. Comprehensive toxicological analysis proved poly-drug use in almost all cases including opiates/opioids, benzodiazepines and other sedatives, antidepressants and other stimulants, also other new psychoactive substances. Alcohol was detected only in three cases. Co-consumed benzodiazepines seem not be able to completely prevent psychotic effects despite their use as first-line treatment for patients with synthetic cathinone poisonings. The study demonstrates that relatively low plasma concentrations of MDPV could be associated with mental impairment which is relevant in the assessment of forensic cases.


Assuntos
Agressão , Benzodioxóis/efeitos adversos , Benzodioxóis/sangue , Drogas Desenhadas/efeitos adversos , Drogas Desenhadas/análise , Pirrolidinas/efeitos adversos , Pirrolidinas/sangue , Violência , Adolescente , Adulto , Cromatografia Líquida , Confusão/induzido quimicamente , Feminino , Alucinações/induzido quimicamente , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Comportamento Paranoide/induzido quimicamente , Transtornos Relacionados ao Uso de Substâncias/complicações , Adulto Jovem , Catinona Sintética
6.
Artigo em Inglês | MEDLINE | ID: mdl-17574934

RESUMO

Since 2005, increasing numbers of seizures of the designer drug of abuse 1-(3-chlorophenyl)piperazine (mCPP) have been reported. This paper describes the unequivocal proof of a mCPP intake. Differentiation from the intake of its precursor drugs trazodone and nefazodone was performed by a systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation. The found mCPP/hydroxy-mCPP ratio indicated altered metabolism of this cytochrome (CYP) 2D6 catalyzed reaction compared to published studies using the same procedure. Although this might be ascribed to a poor metabolizer (PM) phenotype, genotyping revealed no PM genotype but indications for an intermediate metabolizer genotype. However, a PM phenotype could also be caused by drug-drug interactions with CYP2D6 inhibitors or substrates such as the co-consumed cocaine and diltiazem and/or diltiazem metabolites, respectively. In conclusion, the presented data indicate a possible relevance of CYP2D6 polymorphism and/or drug interactions to mCPP toxicokinetics, which is important for risk assessment of this new designer drug of abuse, in particular if it is used as adulterant of CYP2D6 substrates such as cocaine.


Assuntos
Cocaína , Contaminação de Medicamentos , Piperazinas/farmacocinética , Adulto , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Interações Medicamentosas , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Genótipo , Humanos , Fenótipo , Piperazinas/sangue , Piperazinas/urina
7.
Anal Bioanal Chem ; 388(7): 1415-35, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17468860

RESUMO

Determination of drugs of abuse in blood is of great importance in clinical and forensic toxicology. This review describes procedures for detection of the following drugs of abuse and their metabolites in whole blood, plasma or serum: Delta9-tetrahydrocannabinol, 11-hydroxy-Delta9-tetrahydrocannabinol, 11-nor-9-carboxy-Delta9-tetrahydrocannabinol, 11-nor-9-carboxy-Delta9-tetrahydrocannabinol glucuronide, heroin, 6-monoacetylmorphine, morphine, morphine-6-glucuronide, morphine-3-glucuronide, codeine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, N-ethyl-3,4-methylenedioxyamphetamine, 3,4-methylenedioxyamphetamine, cocaine, benzoylecgonine, ecgonine methyl ester, cocaethylene, other cocaine metabolites or pyrolysis products (norcocaine, norcocaethylene, norbenzoylecgonine, m-hydroxycocaine, p-hydroxycocaine, m-hydroxybenzoylecgonine, p-hydroxybenzoylecgonine, ethyl ecgonine, ecgonine, anhydroecgonine methyl ester, anhydroecgonine ethyl ester, anhydroecgonine, noranhydroecgonine, N-hydroxynorcocaine, cocaine N-oxide, anhydroecgonine methyl ester N-oxide). Metabolites and degradation products which are recommended to be monitored for assessment in clinical or forensic toxicology are mentioned. Papers written in English between 2002 and the beginning of 2007 are reviewed. Analytical methods are assessed for their suitability in forensic toxicology, where special requirements have to be met. For many of the analytes sensitive immunological methods for screening are available. Screening and confirmation is mostly done by gas chromatography (GC)-mass spectrometry (MS) or liquid chromatography (LC)-MS(/MS) procedures. Basic information about the biosample assayed, internal standard, workup, GC or LC column and mobile phase, detection mode, and validation data for each procedure is summarized in two tables to facilitate the selection of a method suitable for a specific analytic problem.


Assuntos
Preparações Farmacêuticas/sangue , Detecção do Abuso de Substâncias/métodos , Técnicas de Química Analítica/métodos , Cromatografia , Humanos , Espectrometria de Massas em Tandem , Toxicologia/métodos
8.
Biochem Pharmacol ; 68(5): 947-57, 2004 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15294457

RESUMO

Fenproporex (FP) is known to be N-dealkylated to R(-)-amphetamine (AM) and S(+)-amphetamine. Involvement of the polymorphic cytochrome P450 (CYP) isoform CYP2D6 in metabolism of such amphetamine precursors is discussed controversially in literature. In this study, the human hepatic CYPs involved in FP dealkylation were identified using recombinant CYPs and human liver microsomes (HLM). These studies revealed that not only CYP2D6 but also CYP1A2, CYP2B6 and CYP3A4 catalyzed this metabolic reaction for both enantiomers with slight preference for the S(+)-enantiomer. Formation of amphetamine was not significantly changed by quinidine and was not different in poor metabolizer HLM compared to pooled HLM. As in vivo experiments, blood levels of R(-)-amphetamine and S(+)-amphetamine formed after administration of FP were determined in female Dark Agouti rats (fDA), a model of the human CYP2D6 poor metabolizer phenotype (PM), male Dark Agouti rats (mDA), an intermediate model, and in male Wistar rats (WI), a model of the human CYP2D6 extensive metabolizer phenotype. Analysis of the plasma samples showed that fDA exhibited significantly higher plasma levels of both amphetamine enantiomers compared to those of WI. Corresponding plasma levels in mDA were between those in fDA and WI. Furthermore, pretreatment of WI with the CYP2D inhibitor quinine resulted in significantly higher amphetamine plasma levels, which did not significantly differ from those in fDA. The in vivo studies suggested that CYP2D6 is not crucial to the N-dealkylation but to another metabolic step, most probably to the ring hydroxylation. Further studies are necessary for elucidating the role of CYP2D6 in FP hydroxylation.


Assuntos
Anfetamina/metabolismo , Anfetaminas/metabolismo , Microssomos Hepáticos/metabolismo , Anfetamina/sangue , Anfetaminas/química , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Remoção de Radical Alquila , Dopaminérgicos/química , Dopaminérgicos/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Cinética , Masculino , Conformação Molecular , Ratos , Ratos Wistar
9.
Drug Metab Dispos ; 32(4): 379-81, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15039289

RESUMO

p-Methoxymethamphetamine (PMMA) is a new designer drug, listed in many countries as a controlled substance. Several fatalities have been attributed to the abuse of this designer drug. Previous in vivo studies using Wistar rats had shown that PMMA was metabolized mainly by O-demethylation. The aim of the study presented here was to identify the human hepatic cytochrome P450 (P450) enzymes involved in the biotransformation of PMMA to p-hydroxymethamphetamine. Baculovirus-infected insect cell microsomes, pooled human liver microsomes (pHLMs), and CYP2D6 poor-metabolizer genotype human liver microsomes (PM HLMs) were used for this purpose. Only CYP2D6 catalyzed O-demethylation. The apparent K(m) and V(max) values in baculovirus-infected insect cell microsomes were 4.6 +/- 1.0 microM and 92.0 +/- 3.7 pmol/min/pmol P450, respectively, and 42.0 +/- 4.0 microM and 412.5 +/- 10.8 pmol/min/mg protein in pHLMs. Inhibition studies with 1 microM quinidine showed significant inhibition of the metabolite formation (67.2 +/- 0.6%; p < 0.0001), and comparison of the metabolite formation between pHLMs and PM HLMs revealed significantly lower metabolite formation in the incubations with PM HLMs (87.3 +/- 1.1%; p < 0.0001). According to these studies, CYP2D6 is the major P450 involved in O-demethylation of PMMA.


Assuntos
Anfetaminas/química , Anfetaminas/metabolismo , Biotransformação/efeitos dos fármacos , Citocromo P-450 CYP2D6/isolamento & purificação , Citocromo P-450 CYP2D6/metabolismo , Drogas Desenhadas/metabolismo , Metanfetamina/análogos & derivados , Biotransformação/fisiologia , Cromatografia Líquida/métodos , Citocromo P-450 CYP2D6/química , Drogas Desenhadas/química , Genótipo , Humanos , Espectrometria de Massas/métodos , Metanfetamina/química , Metanfetamina/metabolismo , Metilação/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Estrutura Molecular
10.
Eur J Pharmacol ; 485(1-3): 69-79, 2004 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-14757125

RESUMO

Studies are described on the cytochrome P450 (CYP) isoenzyme dependence of the main metabolic steps of the Eschscholtzia californica alkaloids californine and protopine using rat liver microsomes. Preparations of E. californica are in use as phytopharmaceuticals and as herbal drugs of abuse. CYP isoenzyme dependences were studied using specific chemical inhibitors for CYP1A2, CYP2D1, and CYP3A2 (alpha-naphthoflavone, quinine, and ketoconazole, respectively). CYP2C11 was inhibited by specific antibodies for lack of specific chemical inhibitors. Californine N-demethylation was mainly catalyzed by CYP3A2 and to a minor extent by CYP1A2 and CYP2D1, but not by CYP2C11. CYP2D1 and CYP2C11 were shown to be mainly involved in demethylenation of both, californine and protopine, while CYP1A2 and CYP3A2 showed only minor contribution. Kinetic parameters of the reactions were established. K(m) and V(max) values for the californine N-demethylation were 4.5+/-4.7 microM and 22.9+/-13.7 min/mg protein (high affinity) and 161.3+/-16.7 microM and 311.8+/-39.4 min/mg protein (low affinity), respectively. Californine demethylenation and protopine demethylenation showed substrate inhibition and K(m) and V(max) values were 5.0+/-0.5 and 7.1+/-0.6 microM and 83.3+/-2.6 and 160.7+/-4.0 min/mg protein, respectively.


Assuntos
Alcaloides de Berberina/metabolismo , Sistema Enzimático do Citocromo P-450/fisiologia , Isoquinolinas/metabolismo , Microssomos Hepáticos/enzimologia , Oxirredutases do Álcool , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Benzofenantridinas , Alcaloides de Berberina/química , Citocromo P-450 CYP3A , Família 2 do Citocromo P450 , Relação Dose-Resposta a Droga , Isoenzimas/fisiologia , Isoquinolinas/química , Masculino , Proteínas de Membrana/antagonistas & inibidores , Metilação , Microssomos Hepáticos/metabolismo , Quinina/farmacologia , Ratos , Esteroide 16-alfa-Hidroxilase/antagonistas & inibidores
11.
Biochem Pharmacol ; 67(2): 235-44, 2004 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-14698036

RESUMO

1-(3-Trifluoromethylphenyl)piperazine (TFMPP) is a designer drug with serotonergic properties. Previous studies with male Wistar rats (WI) had shown, that TFMPP was metabolized mainly by aromatic hydroxylation. In the current study, it was examined whether this reaction may be catalyzed by cytochrome P450 (CYP)2D6 by comparing TFMPP vs. hydroxy TFMPP ratios in urine from female Dark Agouti rats, a model of the human CYP2D6 poor metabolizer phenotype (PM), male Dark Agouti rats, an intermediate model, and WI, a model of the human CYP2D6 extensive metabolizer phenotype. Furthermore, the human hepatic CYPs involved in TFMPP hydroxylation were identified using cDNA-expressed CYPs and human liver microsomes. Finally, TFMPP plasma levels in the above mentioned rats were compared. The urine studies suggested that TFMPP hydroxylation might be catalyzed by CYP2D6 in humans. Studies using human CYPs showed that CYP1A2, CYP2D6 and CYP3A4 catalyzed TFMPP hydroxylation, with CYP2D6 being the most important enzyme accounting for about 81% of the net intrinsic clearance, calculated using the relative activity factor approach. The hydroxylation was significantly inhibited by quinidine (77%) and metabolite formation in poor metabolizer genotype human liver microsomes was significantly lower (63%) compared to pooled human liver microsomes. Analysis of the plasma samples showed that female Dark Agouti rats exhibited significantly higher TFMPP plasma levels compared to those of male Dark Agouti rats and WI. Furthermore, pretreatment of WI with the CYP2D inhibitor quinine resulted in significantly higher TFMPP plasma levels. In conclusion, the presented data give hints for possible differences in pharmacokinetics in human PM and human CYP2D6 extensive metabolizer phenotype subjects relevant for risk assessment.


Assuntos
Citocromo P-450 CYP2D6/metabolismo , Drogas Desenhadas/metabolismo , Microssomos Hepáticos/metabolismo , Piperazinas/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Animais , Cromatografia Líquida , Feminino , Humanos , Cinética , Masculino , Espectrometria de Massas , Piperazinas/sangue , Piperazinas/urina , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/sangue , Agonistas do Receptor de Serotonina/urina , Urina/química
12.
Drug Metab Dispos ; 31(8): 979-82, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12867484

RESUMO

4'-Methyl-alpha-pyrrolidinopropiophenone (MPPP) is a new drug of abuse. It is believed to have an abuse potential similar to that of amphetamines. Previous studies with Wistar rats had shown that MPPP was metabolized mainly by hydroxylation in position 4' followed by dehydrogenation to the corresponding carboxylic acid. The aim of the study presented here was to identify the human hepatic cytochrome p450 (p450) enzymes involved in the biotransformation of MPPP to 4'-hydroxymethyl-pyrrolidinopropiophenone. Baculovirus-infected insect cell microsomes and human liver microsomes were used for this purpose. Only CYP2C19 and CYP2D6 catalyzed this hydroxylation. The apparent Km and Vmax values for the latter were 9.8 +/- 2.5 microM and 13.6 +/- 0.7 pmol/min/pmol p450, respectively. CYP2C19 was not saturable over the tested substrate range (2-1000 microM) and interestingly showed a biphasic kinetic profile with apparent Km,1 and Vmax,1 values of 47.2 +/- 12.5 microM and 8.1 +/- 1.4 pmol/min/pmol p450, respectively. Experiments with pooled human liver microsomes also revealed biphasic nonsaturable kinetics with apparent Km,1 and Vmax,1 values of 57.0 +/- 20.9 microM and 199.7 +/- 59.7 pmol/min/mg of protein for the high affinity enzyme, respectively. Incubation of 2 microM MPPP with 3 microM of the CYP2D6-specific inhibitor quinidine resulted in significant (p < 0.01) turnover inhibition (11.8 +/- 1.6% of control). Based on kinetic data corrected for the relative activity factors, CYP2D6 is the enzyme mainly responsible for MPPP hydroxylation, confirmed by CYP2D6 inhibition studies.


Assuntos
Citocromo P-450 CYP2D6/metabolismo , Drogas Desenhadas/metabolismo , Microssomos Hepáticos/metabolismo , Propiofenonas/metabolismo , Pirróis/metabolismo , Animais , Baculoviridae/metabolismo , Cromatografia Líquida , Citocromo P-450 CYP2D6/química , Drogas Desenhadas/química , Humanos , Hidroxilação , Cinética , Espectrometria de Massas
13.
Artigo em Inglês | MEDLINE | ID: mdl-12726842

RESUMO

Eschscholtzia californica preparations are in use as phytopharmaceuticals and as herbal drugs. Studies are described on the metabolism and the toxicological analysis of the Eschscholtzia californica alkaloids californine and protopine in rat urine using gas chromatography-mass spectrometry. The identified metabolites indicated that californine is extensively metabolized by N-demethylation and/or single or double demethylenation with consecutive catechol-O-methylation of one of the hydroxy groups. Protopine, however, only undergoes extensive demethylenation of the 2,3-methylenedioxy group followed by catechol-O-methylation. All phenolic hydroxy metabolites were found to be partly conjugated. The authors' systematic toxicological analysis procedure using full-scan gas chromatography-mass spectrometry after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation allowed the detection of the main metabolites of californine and protopine in rat urine after a dose which should correspond to that of drug users. Therefore, use of Eschscholtzia californica preparations should also be detectable in human urine by the authors' systematic toxicological analysis procedure.


Assuntos
Alcaloides de Berberina/toxicidade , Eschscholzia/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Isoquinolinas/toxicidade , Animais , Benzofenantridinas , Alcaloides de Berberina/urina , Isoquinolinas/urina , Masculino , Ratos
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