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1.
J Pharmacol Exp Ther ; 318(3): 1273-9, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16766719

RESUMO

Although the mu opioid receptor is the primary target of marketed opioid analgesics, several studies suggest the advantageous effect of combinations of mu and delta opioids. The novel compound RWJ-394674 [N,N-diethyl-4-[(8-phenethyl-8-azabicyclo]3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide]; bound with high affinity to the delta opioid receptor (0.2 nM) and with weaker affinity to the mu opioid receptor (72 nM). 5'-O-(3-[(35)S]-thio)triphosphate binding assay demonstrated its delta agonist function. Surprisingly given this pharmacologic profile, RWJ-394674 exhibited potent oral antinociception (ED(50) = 10.5 micromol/kg or 5 mg/kg) in the mouse hot-plate (48 degrees C) test and produced a moderate Straub tail. Antagonist studies in the more stringent 55 degrees C hot-plate test demonstrated the antinociception produced by RWJ-394674 to be sensitive to the nonselective opioid antagonist naloxone as well as to the delta- and mu-selective antagonists, naltrindole and beta-funaltrexamine, respectively. In vitro studies demonstrated that RWJ-394674 was metabolized by hepatic microsomes to its N-desethyl analog, RWJ-413216 [N-ethyl-4-[(8-phenethyl-8-azabicyclo[3.2.1]oct-3-ylidene)-phenylmethyl]-benzamide], which, in contrast to RWJ-394674, had a high affinity for the mu rather than the delta opioid receptor and was an agonist at both. Pharmacokinetic studies in the rat revealed that oral administration of RWJ-394674 rapidly gave rise to detectable plasma levels of RWJ-413216, which reached levels equivalent to those of RWJ-394674 by 1 h. RWJ-413216 itself demonstrated a potent oral antinociceptive effect. Thus, RWJ-394674 is a delta opioid receptor agonist that appears to augment its antinociceptive effect through biotransformation to a novel mu opioid receptor-selective agonist.


Assuntos
Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Administração Oral , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Feminino , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
2.
Xenobiotica ; 36(6): 551-65, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16769648

RESUMO

The in vivo metabolism of both tramadol-N-oxide (TNO) and tramadol was investigated in urine pools obtained from 0-24 h after a single 300 mg kg-1 oral dose administration of each compound to specific pathogen-free and axenic mice. Unchanged TNO (< or =42% of the initial drug sample), tramadol, and 23 metabolites from TNO-treated mice and unchanged tramadol (< or =15% of the sample) plus 20 metabolites from tramadol-treated mice were profiled, quantified and tentatively identified on the basis of atmospheric pressure ionization mass spectrometry (API-MS) and tandem mass spectrometry (MS/MS) data. Of the tramadol metabolites, five (M1-5) have been previously identified in mice. Of the tramadol and TNO metabolites, six (M18-23) are new metabolites. The tramadol and TNO metabolites were formed via the following seven metabolic pathways: N-oxide reduction (TNO), O/N-demethylation, cyclohexyloxidation, oxidative N-dealkylation, dehydration (TNO), N-oxidation (tramadol), and glucuronidation. Pathways 1-3 appear to be predominant steps forming four major O/N-desmethyl and hydroxycyclohexyl metabolites, and in conjunction with pathway 7, formed six minor glucuronides. Both tramadol-N-oxide and tramadol are extensively metabolized in mice, and no significant qualitative or quantitative differences in metabolism were observed between specific pathogen-free and axenic mice with the exception of a greater amount of unchanged TNO in axenic mice than in specific pathogen-free mice, more M2 in specific pathogen-free mice than in axenic mice in the TNO-dosed mice, and visa versa for M2 of tramadol-dosed mice.


Assuntos
Analgésicos Opioides/farmacocinética , Tramadol/análogos & derivados , Analgésicos Opioides/administração & dosagem , Animais , Biotransformação , Masculino , Camundongos , Especificidade da Espécie , Organismos Livres de Patógenos Específicos , Espectrometria de Massas por Ionização por Electrospray , Tramadol/administração & dosagem , Tramadol/farmacocinética
3.
Eur J Drug Metab Pharmacokinet ; 31(4): 271-6, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17315538

RESUMO

The In vitro metabolism of two alpha-1A-adrenergic antagonists, RWJ-69205 and RWJ-69471 (phthalimide-phenylpiperazine analogs), was assessed after 30 and 60 min incubations with rat, dog and human hepatic S9 fractions in the presence of an NADPH-generating system. Unchanged RWJ-69205 (> or = 72% of the sample in all species) plus 3 metabolites from the RWJ-69205 incubations, and unchanged RWJ-69471 (> or = 60% of the sample in all species) and 7 metabolites from the RWJ-69471 incubations, were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The formation of RWJ-69205 and RWJ-69471 metabolites are via the following five metabolic pathways: 1. phenylhydroxylation, 2. O-dealkylation, 3. oxidative N-dealkylation, 4. N-dephenylation, and 5. dehydration. Pathway 1 formed 2 major/moderate hydroxy-phenyl metabolites of 2 analogs (4-17%) in all species, and pathway 2 produced 2 O-desisopropyl metabolites of 2 analogs in major/moderate (7-16%) in rat and human, and in trace (< 1%) in dog; in conjunction with pathway 1, yielded a minor diphenolic metabolite (< 1-2%) in RWJ-69471. Pathway 3 formed a minor N-dealkylated metabolite, isopropoxyphenyl piperazine (< 1-6%) in all species of 2 analogs. Pathways 4 and 5 produced 2 minor N-desphenyl metabolite and dehydrated metabolite, respectively, in rat and human S9 (< or = 1-2%) in RWJ-69471. Both RWJ-69205 and RWJ-69471 were less extensively metabolized in the dog. However, rat and human appeared to metabolize RWJ-69471 more extensively than RWJ-69205 in this hepatic system.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/metabolismo , Fígado/metabolismo , Ftalimidas/química , Ftalimidas/metabolismo , Piperazinas/química , Piperazinas/metabolismo , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão/métodos , Remoção de Radical Alquila , Cães , Humanos , Hidroxilação , Técnicas In Vitro , Isoindóis , Estrutura Molecular , Oxirredução , Ftalimidas/farmacologia , Piperazinas/farmacologia , Ratos , Receptores Adrenérgicos alfa 1 , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Fatores de Tempo
4.
Eur J Drug Metab Pharmacokinet ; 30(3): 151-64, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16250251

RESUMO

The metabolism and excretion of 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate (TOPAMAX, topiramate, TPM) have been investigated in animals and humans. Radiolabeled [14C] TPM was orally administered to mice, rats, rabbits, dogs and humans. Plasma, urine and fecal samples were collected and analyzed. TPM and a total of 12 metabolites were isolated and identified in these samples. Metabolites were formed by hydroxylation at the 7- or 8-methyl of an isopropylidene of TPM followed by rearrangement, hydroxylation at the 10-methyl of the other isopropylidene, hydrolysis at the 2,3-O-isopropylidene, hydrolysis at the 4,5-O-isopropylidene, cleavage at the sulfamate group, glucuronide conjugation and sulfate conjugation. A large percentage of unchanged TPM was recovered in animal and human urine. The most dominant metabolite of TPM in mice, male rats, rabbits and dogs appeared to be formed by the hydrolysis of the 2,3-O-isopropylidene group.


Assuntos
Anticonvulsivantes/metabolismo , Frutose/análogos & derivados , Transtornos de Enxaqueca/tratamento farmacológico , Adulto , Animais , Cães , Feminino , Frutose/metabolismo , Humanos , Masculino , Camundongos , Coelhos , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Especificidade da Espécie , Topiramato
5.
Eur J Drug Metab Pharmacokinet ; 30(1-2): 105-11, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16010869

RESUMO

The In vitro metabolism of the alpha-1A-adrenergic antagonist, RWJ-69597, an analog of pyridine-phenylpiperazines, was conducted after incubation with rat, dog and human hepatic S9 fractions in the presence of an NADPH-generating system. Unchanged RWJ-69597 (> or =43% of the sample in all species) plus 9 metabolites were profiled, quantified, and tentatively identified on the basis of API-MS and MS/MS data. The four metabolic pathways for the formation of RWJ-69597 metabolites are: 1. methyl/phenyl/piperazinylhydroxylation, 2. N/Odealkylation, 3. N-dephenylation, and 4. dehydration. Pathway 1 formed 1 major (8-36%) and 3 minor (<1-3%) hydroxylated metabolites. Pathway 2 produced 2 moderate/minor N/O-dealkylated metabolites (<1- < or =11%), and in conjunction with pathway 1, formed 1 minor diol metabolites (< or =2%). Pathways 3 and 4 generated 2 minor metabolites, N-desphenyl RWJ-69597 (< or =4%) and dehydrated RWJ-69597 (< or =2%), respectively. RWJ-69597 is more extensively metabolized in the rat than the dog or the human in this hepatic system.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/metabolismo , Microssomos Hepáticos/metabolismo , Piperazinas/metabolismo , Piridinas/metabolismo , Animais , Cães , Humanos , Espectrometria de Massas , Ratos
6.
Eur J Drug Metab Pharmacokinet ; 30(1-2): 113-20, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16010870

RESUMO

The in vitro and in vivo metabolism of RWJ-69442, an alpha-1A-adrenergic receptor antagonist, was investigated after incubation with rat, dog, and human hepatic S9 fractions in the presence of NADPH-generating system, and a single oral/iv dose administration to rats (oral: 100 mg/kg; iv: 10 mg/kg). Unchanged RWJ-69442 (> or =30% of the sample in vitro; < or =47% of the sample in vivo) plus 14 metabolites were profiled, quantified and tentatively identified on the basis of API-MS and MS/MS data. The metabolic pathways for RWJ-69442 are proposed via the 4 steps: 1. phenyl/piperazinylhydroxylation, 2. N/O-dealkylation, 3. N-dephenylation, and 4. dehydration. Pathway 1 formed OH-phenyl-RWJ-69442 (M1, 4-32% in vitro & in vivo), and diOH-RWJ-69442 (M4, <1-4% in vitro & in vivo). Pathway 2 generated O-desisopropyl-RWJ-69442 (M2, <1-21% in vitro & in vivo), N-desmethyl-RWJ-69442 (M3, 2-3% in vitro & in vivo), N-desmethyl-M2 (M6, 1-8% in vitro & in vivo), and N-dealkylated RWJ-69442 (M9, < or =1-17% in vitro & in vivo), and in conjunction with pathway 1 produced 6 minor to major oxidized metabolites, OH-M2 (M5, 1-2% in vitro), OH-M3 (M11, 4-6% in vivo), OH-M9 (M10, <1-34% in vitro & in vivo), O-desisopropyl-M9 (M12, 3-21% in vivo), O-desisopropyl-M10 (M13,2-12% in vivo), and dehydro-M13 (M14, 25% in vivo). Pathways 3 and 4 formed 2 minor metabolites, N-desphenyl-RWJ-69442 (M7, <1-12% in vitro & in vivo) and dehydrated-RWJ-69442 (M8, <1-2% in vitro), respectively. RWJ-69442 is extensively metabolized in vitro in the rat and human (except dog), and in vivo in the rat.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/metabolismo , Microssomos Hepáticos/metabolismo , Ftalimidas/metabolismo , Piperazinas/metabolismo , Animais , Cães , Humanos , Espectrometria de Massas , Ratos
7.
Xenobiotica ; 34(6): 591-606, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15277018

RESUMO

1. The in vivo metabolism of the antineoplastic and immunosuppressive drug 2-CdA (Leustatin) was investigated in mice, monkeys and humans after a single subcutaneous dose of cladribine 60 mg kg(-1) to eight male and eight female mice and 10 mg kg(-1) to one male and one female monkey, and an intravenous infusion dose of cladribine 22-45 mg(-1) per subject to 12 male patients. 2. Plasma (1 h), red blood cells (1 h) and faecal samples (0-24 h) were obtained from mice and monkeys, and urine samples (0-24 h) were obtained from these species and humans. 3. Unchanged cladribine (urine: 47% of the sample in human; 60% of the sample in mouse; 73% of the sample in monkey) and 10 metabolites, consisting of four phase I metabolites (M1-3, M7) and six phase II metabolites -- five glucuronides (M4, M6, M8-10) and one sulfate (M5) -- were profiled, characterized and tentatively identified in plasma, red blood cells, and faecal and urine samples on the basis of API ionspray-mass spectrometry (MS) and MS/MS data. 4. Metabolites were formed via the following three metabolic pathways: oxidative cleavage at the adenosine and deoxyribose linkage (A); oxidation at adenosine/deoxyribose (B); and conjugation (C). 5. Pathways A and B appear to be major steps, forming four oxidative/cleavage metabolites (M1-3, M7) (each 3-20% of the sample). 6. Pathway C along or in conjunction with pathways A and B produced cladribine glucuronide, cladribine sulfate and four glucuronides of oxidative/cleavage metabolites in minor/trace quantities (each < or = 5% of the sample). 7. In addition, the in vitro metabolism of cladribine was conducted using rat and human liver microsomal fractions in the presence of an beta-nicotinamide adenine dinucleotide phosphate-generating system. Unchanged cladribine (> or = 90% of the sample) plus three minor metabolites, M1-3 (each < 8% of the sample), were profiled and tentatively identified by thin-layer chromatography and MS data. 8. Cladribine is not extensively metabolized in vitro and in vivo in all species. However, humans appear to metabolize cladribine to a greater extent than other animals.


Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Cladribina/metabolismo , Cladribina/farmacocinética , Imunossupressores/metabolismo , Imunossupressores/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/urina , Cladribina/administração & dosagem , Cladribina/urina , Feminino , Haplorrinos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/urina , Masculino , Espectrometria de Massas , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular
8.
Eur J Drug Metab Pharmacokinet ; 29(4): 257-62, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15726887

RESUMO

The In vitro metabolism of the anxiolytic agent, RWJ-51521 was conducted after incubation with human hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-51521 (30% of the sample) and a total of 11 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)-MS/MS data. The 4 proposed metabolic pathways for RWJ-51521 are: (1) N/O-dealkylation, (2) phenylhydroxylation, (3) pyrido-oxidation, and (4) dehydration. Pathway 1 formed 2 major and 3 minor N/O-desalkyl metabolites (M1 & M3, 50%) and in conjunction with pathway 4, formed 2 moderate dehydrated metabolites (M4 & M5, 14%). Pathways 2 and 3 alone, and in conjunction with pathway 4, produced 4 minor metabolites (each < or =2%). RWJ-51521 is extensively metabolized in human hepatic S9 fraction.


Assuntos
Amidas/metabolismo , Ansiolíticos/metabolismo , Benzimidazóis/metabolismo , Fígado/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos , Ansiolíticos/análise , Aziridinas , Benzimidazóis/análise , Humanos , Espectrometria de Massas/métodos
9.
Eur J Drug Metab Pharmacokinet ; 29(4): 263-8, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15726888

RESUMO

The in vitro and in vivo metabolism of the nonbenzodiazepine anxiolytic agent, RWJ-51204 was investigated after incubation with mice, rat, dog, monkey, and human hepatic S9 fractions in the presence of NADPH-generating system, and a single oral dose administration to rats (100 mg/kg), dogs (5 mg/kg), and humans (2.5 mg/subject). Plasma and red blood cells (2 h, rat) and urine samples (0-24 h, rat, dog and human) were obtained postdose. Unchanged RWJ-51204 (39-93% of the sample in vitro; < or =5% of the sample in vivo) plus 14 metabolites were profiled, quantified and tentatively identified on the basis of API-MS and MS/MS data, and by comparison of synthetic samples. The in vitro and in vivo metabolic pathways for RWJ-51204 are proposed, and the metabolite formations are via the following five pathways: 1. phenyl oxidation, 2. pyrido-oxidation, 3. N-deethoxymethylation, 4. dehydration, and 5. glucuronidation. Pathway 1 formed 4-hydroxy-2-fluoro-phenyl-RWJ-51204 (M1, 7-24% in vitro; 5-60% in vivo) in major amounts, OH-benzimidazole-RWJ-51204 (M2, 5-8% in vitro and in vivo) and diOH-phenyl-RWJ-51204 (< or =5-16% in vitro and in vivo); in conjunction with pathway 5 produced M1 glucuronide (60% in rat & dog; 17% in human), M2 glucuronide (16% in human). Pathways 2-4 formed minor/trace oxidized, and dehydrated metabolites. RWJ-51204 is extensively metabolized in vitro (except dog) and in vivo in rats, dogs and humans.


Assuntos
Ansiolíticos/metabolismo , Imidazóis/metabolismo , Fígado/metabolismo , Piridonas/metabolismo , Animais , Ansiolíticos/química , Cães , Feminino , Haplorrinos , Humanos , Imidazóis/química , Masculino , Camundongos , Piridonas/química , Ratos , Especificidade da Espécie
10.
Eur J Drug Metab Pharmacokinet ; 28(2): 101-5, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12877566

RESUMO

RWJ-37874, an analogue of aroyl(aminoacyl)pyrrole, is a new analgesic agent. The in vitro metabolism of RWJ-37874 was conducted using rat and human hepatic S9 in the presence of an NADPH generating system, and API-ionspray-MS and MS/MS techniques for metabolite profiling and identification. Unchanged RWJ-37874 (66 & 86% of the sample in rat & human, respectively) plus four metabolites were profiled and tentatively identified on the basis of MS data. RWJ-37874 metabolites were formed via the following two metabolic pathways: 1. oxidative N-deethylation, and 2. pyrrole-oxidation. Pathway 1 produced a mayor and a minor metabolites, N-desethyl-RWJ-37874 (M1; 34% in rat; 13% in human) and N,N-didesethyl-RWJ-37874 (M3; <0.5% in both species), respectively. Pathway 2 formed hydroxypyrrole-RWJ-37874 (M2; <0.5% in all species), and in conjunction with step 1, formed hydroxy-M1 (M4; <0.5% in rat). RWJ-37874 is substantially metabolized in rat and human hepatic S9 fractions. However, rat appears to metabolize RWJ-37874 more extensively than human via N-dealkylation forming N-desethyl-RWJ-37874 as a major metabolite.


Assuntos
Analgésicos/química , Analgésicos/metabolismo , Fígado/metabolismo , Pirróis/metabolismo , Analgésicos/análise , Animais , Humanos , Masculino , Pirróis/química , Ratos
11.
Eur J Drug Metab Pharmacokinet ; 28(2): 107-11, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12877567

RESUMO

RWJ-51784, an analogue of phenyl isoindoles, is a new analgesic agent. The in vitro metabolism of RWJ-51784 was conducted using rat, dog and human hepatic S9 in the presence of an NADPH generating system, and API-ionspray-MS and MS/MS techniques for the metabolite profiling and identification. Unchanged RWJ-51784 (82, 80 & 86% of the sample in rat, dog & human, respectively) plus 6 metabolites were profiled and tentatively identified on the basis of MS data. RWJ-51784 metabolites were formed via the following 3 metabolic pathways: 1. N-demethylation, 2. phenylhydroxylation, and 3. isoindole-oxidation. Pathway 1 produced a moderate or minor metabolite, N-desmethyl-RWJ-51784 (M1; 6% in rat; 5% in dog, 2% in human). Pathway 2 formed 4-hydroxyphenyl-RWJ-51784 (M2; 3-6% in all species). Step 3 formed 2 isoindole-oxidized metaboliotes, OH-indole (M3; 7-8% in all species) and oxo-indole (M4; <1% in all species)-RWJ-51784, and in conjunction with pathway 2 produced 2 trace metabolites, OH-phenyl-OH-isoindole (M5) and OH-phenyl-oxo-isoindole (M6) metabolites. RWJ-51784 is not extensively metabolized in rat, dog and human hepatic S9 fractions.


Assuntos
Analgésicos/química , Analgésicos/metabolismo , Carbazóis/metabolismo , Fígado/metabolismo , Pirróis/metabolismo , Animais , Biotransformação/fisiologia , Carbazóis/química , Cães , Humanos , Masculino , Pirróis/química , Ratos
12.
Eur J Drug Metab Pharmacokinet ; 28(4): 279-86, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14743969

RESUMO

The In vitro biotransformation of the antipsychotic agent, mazapertine was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged mazapertine (42% of the sample) plus 12 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)-MS/MS data. The proposed metabolic pathways for mazapertine are proposed, and the 6 metabolic pathways are: (1) phenylhydroxylation, (2) piperidyl oxidation, (3) O-dealkylation, (4) N-dephenylation, (5) oxidative N-debenzylation, and (6) dehydration. Pathways 1 to 3 formed 4-OH-phenyl (M1, 10%) and 4-OH-piperidyl (M2, 9%)-mazapertine, O-desisopropyl mazapertine (M3, 17%), and N-desbenzoylpiperidine-mazapertine (M8, 14%) as 4 major metabolites. Mazapertine is extensively metabolized in rat hepatic S9 fraction.


Assuntos
Antipsicóticos/farmacocinética , Fígado/metabolismo , Piperazinas/farmacocinética , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Técnicas In Vitro , Espectrometria de Massas , Metilação , Ratos , Frações Subcelulares/metabolismo
13.
Xenobiotica ; 32(11): 949-62, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12487725

RESUMO

1. In vitro studies have been carried out to investigate the metabolic pathways and identify the hepatic cytochrome P450 (CYP) enzymes involved in etoperidone (Et) metabolism. 2. Ten in vitro metabolites were profiled, quantified and tentatively identified after incubation with human hepatic S9 fractions. Et was metabolized via three metabolic pathways: (A) alkyl hydroxylation to form OH-ethyl-Et (M1); (B) phenyl hydroxylation to form OH-phenyl-Et (M2); and (C) N-dealkylation to form 1-m-chlorophenylpiperazine (mCPP, M8) and triazole propyl aldehyde (M6). Six additional metabolites were formed by further metabolism of M1, M2, M6 and M8. 3. Kinetic studies revealed that all metabolic pathways were monophasic, and the pathway leading to the formation of OH-ethyl-Et was the most efficient at eliminating the drug. On incubation with microsomes expressing individual recombinant CYPs, formation rates of M1-3 and M8 were 10-100-fold greater for CYP3A4 than that for other CYP forms. The formation of these metabolites was markedly inhibited by the CYP3A4-specific inhibitor ketoconazole, whereas other CYP-specific inhibitors did not show significant effects. In addition, the production of M1-3 and M8 was strongly correlated with CYP3A4-mediated testosterone 6beta-hydroxylase activities in 13 different human liver microsome samples. 4. Dealkylation of the major metabolite M1 to form mCPP (M8) was also investigated using microsomes containing recombinant CYP enzymes. The rate of conversion of M1 to mCPP by CYP3A4 was 503.0 +/- 3.1 pmole nmole(-1) min(-1). Metabolism of M1 to M8 by other CYP enzymes was insignificant. In addition, this metabolism in human liver microsomes was extensively inhibited by the CYP3A4 inhibitor ketoconazole, but not by other CYP-specific inhibitors. In addition, conversion of M1 to M8 was highly correlated with CYP3A4-mediated testosterone 6beta-hydroxylase activity. 5. The results strongly suggest that CYP3A4 is the predominant enzyme-metabolizing Et in humans.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Fígado/enzimologia , Trazodona/análogos & derivados , Trazodona/farmacologia , Cromatografia Líquida , Sistema Enzimático do Citocromo P-450/metabolismo , DNA Complementar/metabolismo , Relação Dose-Resposta a Droga , Humanos , Cinética , Fígado/efeitos dos fármacos , Espectrometria de Massas , Microssomos Hepáticos/enzimologia , Modelos Químicos , Isoformas de Proteínas , Proteínas Recombinantes/metabolismo , Esteroide Hidroxilases/metabolismo , Trazodona/metabolismo
14.
Eur J Drug Metab Pharmacokinet ; 27(3): 193-7, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12365201

RESUMO

Tramadol-N-oxide (TNO, RWJ-38705) is a new analgesic agent, which is believed to produce its analgesic effect following metabolic conversion to tramadol. In the present study, API ionspray-MS and MS/MS techniques were used to profile the in vitro metabolism of TNO in mouse, rat, and human hepatic S9 fractions in the presence of an NADPH generating system. Unchanged TNO represented 60, 24, and 26% of the sample in mouse, rat, and human, respectively. Tramadol, and seven other metabolites were profiled and tentatively identified on the basis of MS analysis and by comparison to synthetic reference samples. TNO metabolites were formed via four Phase I reactions: (1) N-oxide reduction, (2) O-demethylation, (3) N-demethylation, and (4) cyclohexylhydroxylation. TNO was found to be substantially metabolized in hepatic S9 from all three species. The metabolism of TNO to tramadol via N-oxide reduction was greater in rat and human than in mouse.


Assuntos
Analgésicos Opioides/metabolismo , Tramadol/análogos & derivados , Tramadol/metabolismo , Analgésicos Opioides/análise , Analgésicos Opioides/química , Animais , Humanos , Fígado/metabolismo , Masculino , Camundongos , Ratos , Especificidade da Espécie , Tramadol/análise , Tramadol/química
15.
Xenobiotica ; 32(5): 411-25, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12065063

RESUMO

1. Metabolism of the analgesic agent tramadol hydrochloride has been investigated after a single oral administration of tramadol to three male volunteers (100 mg/subject), and a urine pool (4-12h) was obtained. 2. Unchanged tramadol and a total of 23 metabolites, consisting of 11 Phase I metabolites (M1-11) and 12 conjugates (seven glucuronides, five sulphates), were profiled, characterized and tentatively identified in urine on the basis of API ionspray-MS and MS/MS data. 3. Of the metabolites, five (M1-5) had been previously identified. 4. The metabolites were formed via the following six metabolic pathways: (1) O-demethylation, (2) N-demethylation, (3) cyclohexyl oxidation, (4) oxidative N-dealkylation, (5) dehydration and (6) conjugation. 5. Pathways 1-3 appear to be major routes, forming seven O-desmethyl/N-desmethyl and hydroxycyclohexyl metabolites. 6. Pathways 1-3 in conjunction with pathway 6 produced seven glucuronides along with five sulphates. 7. In addition, the in vitro metabolism of tramadol was conducted using a human liver microsomal fraction in the presence of an NADPH-generating system. Unchanged tramadol (82% of the sample) plus eight metabolites (M1, M2, M4-6, tramadol-N-oxide (M31), OH-cyclohexyl-M1 (M32) and dehydrated tramadol-N-oxide), were profiled and tentatively identified on the basis of MS and MS/MS data.


Assuntos
Analgésicos Opioides/metabolismo , Tramadol/metabolismo , Administração Oral , Adolescente , Adulto , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/química , Glucuronídeos/química , Glucuronídeos/metabolismo , Humanos , Técnicas In Vitro , Masculino , Espectrometria de Massas , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Tramadol/administração & dosagem , Tramadol/análogos & derivados , Tramadol/química
16.
Xenobiotica ; 31(7): 423-41, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11531006

RESUMO

1. Metabolism of the analgesic agent, tramadol hydrochloride, was investigated after a single oral administration of 14C-tramadol to four rats (50)mgkg(-1) and two dogs (20)mg kg(-1). 2. Recovery of total radioactivity in rat and dog urine samples over 24 h was 73 and 65% of the radioactive dose, respectively. 3. Unchanged tramadol and a total of 24 metabolites, consisting of 16 Phase I metabolites and eight conjugates (seven glucuromides, one sulphate), were isolated and tentatively identified, which accounted for > 52% of the dose in urine of both species. 4. Of the metabolites, five (M1-5) were previously identified. 5. The metabolites were formed via the following six metabolic pathways: O-demethylation, N-demethylation, cyclohexyl oxidation, oxidative N-dealkylation, dehydration and conjugation. 6. Pathways 1-3 appear to be major steps, forming seven O-desmethyl/N-desmethyl and hydroxy-cyclohexyl metabolites in major quantities. 7. Pathways 1-3 in conjunction with pathway 6 produced four glucuronides along with four minor conjugates. 8. In addition, the in vitro metabolism of tramadol was conducted using rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged tramadol (30% of the sample) plus nine metabolites, M1-7, tramadol-N-oxide (M31) and OH-cyclohexyl-M1 (M32), were profiled and tentatively identified based on MS and MS/MS data.


Assuntos
Analgésicos Opioides/farmacocinética , Tramadol/farmacocinética , Analgésicos Opioides/urina , Animais , Cromatografia em Camada Fina , Cães , Feminino , Glucuronídeos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Modelos Químicos , Ratos , Ratos Wistar , Especificidade da Espécie , Fatores de Tempo , Tramadol/urina
17.
J Pharm Biomed Anal ; 24(2): 307-16, 2000 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-11130209

RESUMO

The in vitro biotransformation of the antipsychotic agent, RWJ-46344 was studied after incubation with rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged RWJ-46344 (approximately 37% of the sample) plus 12 metabolites were profiled, quantified, and tentatively identified on the basis of API (ionspray)-MS/MS/MS data. The proposed metabolic pathways for RWJ-46344 are proposed, and the six metabolic pathways are 1, O-dealkylation; 2, piperidinyl oxidation; 3, N-debenzylation; 4, phenyl hydroxylation; 5, dehydration; and 6, reduction. Pathways 1 to 3 formed O-desisopropyl RWJ-46344 (M3, approximately 13% of the sample) and its hydroxy-metabolite (M5, approximately 8%), hydroxypiperidinyl RWJ-46344 (M1, approximately 5%) and a phenylpiperidinyl metabolite (M8, approximately 24%) as major and moderate metabolites. Eight minor metabolites (each < 2%) were formed via a combination of six steps. RWJ-46344 is metabolized substantially by this rat hepatic system.


Assuntos
Antipsicóticos/farmacocinética , Espectrometria de Massas/métodos , Piperidinas/farmacocinética , Animais , Biotransformação , Fígado/metabolismo , Ratos
18.
Curr Drug Metab ; 1(3): 255-70, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11465048

RESUMO

Compound biotransformation is a very important research area for drug discovery and development. In this review, publications from the metabolism studies of ten compounds, seven CNS and three cardiovascular agents, from the Johnson & Johnson Corp. were reviewed. The seven CNS compounds are: three antipsychotic agents, mazapertine (arypiperazine analog), RWJ-46344 (arypiperidine analog) and risperidone (aryisoxazole-piperidine analog), one antidepressant, etoperidone (arypiperazine analog), one anxiolytic agent, fenobam (aryimidazole urea analog), one muscle relaxant, xilobam (pyrrolidinylidene urea analog), and one antiepileptic agent, topiramate (fructopyranose sulfamate analog). The three cardiovascular agents are: two arylalkylamine calcium channel blockers, bepridil and RWJ-26240, and one thioindolaminidine antianginal agent, RWJ-34130. Other antipsychotic and antidepressant agents with similar analogs (ziprasidone, trazodone and nefazodone) as well as other similar analogs of calcium channel blockers (verapamil) are discussed. In this article, excretion and metabolism (in vitro, in vivo) of compounds are reviewed from the CNS agents to the cardiovascular agents, including structures of parent compounds, their metabolites, metabolic pathways, and methods for the isolation, profiling, quantification and structural identification of unchanged compounds and metabolites. Pharmacological activities of parent compounds and their metabolites are also briefly discussed.


Assuntos
Fármacos Cardiovasculares/farmacocinética , Fármacos do Sistema Nervoso Central/farmacocinética , Animais , Biotransformação , Humanos
19.
Xenobiotica ; 29(11): 1089-100, 1999 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-10598744

RESUMO

1. In vitro metabolism of the antiprogestin drug mifepristone (RU-486) was studied after incubation with rat, monkey and human hepatic S9 fractions in the presence of an NADPH-generating system. 2. Unchanged mifepristone (approximately 45% of the sample(s) in rat; approximately 70% in monkey; approximately 65% in human) plus six metabolites, three known and three new, were profiled, quantified and tentatively identified on the basis of MS and MS/MS data. 3. The proposed metabolic pathways for mifepristone are proposed, and the two metabolic steps are (A) N-demethylation and (B) methyl oxidation. 4. Step A formed N-desmethyl mifepristone (M1) in major amounts (approximately 35% s in rat, 16% in monkey and human) and N,N-didesmethyl mifepristone (M2) in minor amounts (< 5% s in all species). Step B, or in conjunction with step A, produced four minor/trace metabolites, namely hydroxymethyl mifepristone (M3), hydroxymethyl M1 (M4), hydroxymethyl M2 (M5) and formyl mifepristone (M6).


Assuntos
Fígado/metabolismo , Mifepristona/farmacocinética , Frações Subcelulares/metabolismo , Acetatos/química , Animais , Biotransformação , Haplorrinos , Humanos , Técnicas In Vitro , Masculino , Ratos , Especificidade da Espécie
20.
Xenobiotica ; 29(5): 453-66, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10379984

RESUMO

1. Biotransformation of the antipsychotic agent, mazapertine, was studied after a single oral administration of 14C-mazapertine succinate (10 mg/kg, free base) to six beagle dogs (three male, three female). 2. Following oral administration of 14C-mazapertine, plasma (0-48 h), urine (0-7 days), and faeces (0-7 days) were collected. Recoveries of total radioactivity in urine and faeces were 26.9 and 62.0% of the dose, respectively. 3. Unchanged mazapertine plus 14 metabolites were isolated and identified, which accounted for > 60% of the sample radioactivity in the plasma, 17% of the dose in urine and 28% of the dose in faecal extract. 4. Unchanged mazapertine accounted for < 4% of the radioactive dose in excreta samples and < 21% of the sample radioactivity present in plasma samples. 5. Seven metabolic pathways for the formation of metabolites were identified including: (1) phenyl hydroxylation, (2) piperidyl oxidation, (3) O-dealkylation, (4) N-dephenylation, (5) oxidative N-debenzylation, (6) depiperidylation and (7) conjugation. 6. Pathways 1, 2, 5 and 6 produced 4-OH-piperidyl, OH-phenyl-OH-piperidyl, carboxybenzoyl piperidine and depiperidyl analogues of mazapertine as major metabolites.


Assuntos
Antipsicóticos/metabolismo , Piperazinas/metabolismo , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/farmacocinética , Biotransformação , Radioisótopos de Carbono , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Cães , Fezes/química , Feminino , Masculino , Espectrometria de Massas/métodos , Piperazinas/administração & dosagem , Piperazinas/farmacocinética
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