RESUMEN
The transdermally applied dopamine receptor agonist rotigotine is extensively metabolized in the liver. An open-label, parallel-group study was conducted to evaluate the effects of moderate hepatic impairment on the pharmacokinetics, safety and tolerability of rotigotine. Eight subjects with normal hepatic function and nine with moderate hepatic impairment (Child-Pugh class B) received one rotigotine transdermal patch (providing a dose of 2 mg/24 h) daily for 3 days with a 24-h patch-on period. Blood and urine samples were collected to evaluate pharmacokinetic parameters characterizing drug bioavailability and elimination. Primary variables included plasma and urine concentrations of unconjugated rotigotine (active parent compound) and total rotigotine (unconjugated rotigotine plus sulfate and glucuronide conjugates) under steady-state (SS) conditions. For unconjugated rotigotine, point estimates for the ratios of AUC(0-24)SS and C max,SS between the two groups (normal vs. impaired hepatic function) were near 1: AUC(0-24)SS, 0.90 (90 % CI 0.59, 1.38) and C max,SS, 0.94 (90 % CI 0.66, 1.35); t max,SS and t 1/2 were lower in subjects with hepatic impairment, while renal clearance was unaffected and overall clearance was higher. For total rotigotine, C max,SS was higher in subjects with hepatic impairment compared with those with normal hepatic function (P = 0.0239, ANOVA). A tendency to reduced non-renal clearance was observed in subjects with hepatic impairment, consistent with their higher plasma concentrations of total rotigotine. Thus, moderate hepatic impairment did not influence the pharmacokinetics of unconjugated rotigotine under steady-state conditions suggesting that dose adjustment will not be required for patients with mild or moderate hepatic insufficiency. In addition, the rotigotine patch was well tolerated in subjects with moderate hepatic impairment.
Asunto(s)
Agonistas de Dopamina/farmacocinética , Hepatopatías/metabolismo , Hígado/metabolismo , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Administración Cutánea , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Biotransformación , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/efectos adversos , Agonistas de Dopamina/sangre , Agonistas de Dopamina/orina , Humanos , Hungría , Hepatopatías/diagnóstico , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Eslovaquia , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/efectos adversos , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/orina , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Tiofenos/sangre , Tiofenos/orina , Parche TransdérmicoRESUMEN
7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN ) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-benzopyran (HHCB) are polycyclic musks widely used as fragrance ingredients in consumer products. Because their metabolic fate following systemic exposure is not fully characterized, disposition and excretion of (14)C-AHTN- and (14)C-HHCB-derived radioactivity were studied in Sprague-Dawley rats and domestic pigs following a single intravenous dose. Rats administered with AHTN or HHCB excreted 21% or 28% of the radioactivity in urine and 67% or 61% in feces, respectively, within 7 days. In pigs administered AHTN or HHCB, 86% or 74% of the dose was excreted in the urine, and 12% or 15% in feces, respectively, during the 14-day collection period. Radioactivity in the whole blood and plasma of both species and tissues of rats declined steadily until the end of the study (28 days) for both the materials. Radioactivity in rat adipose tissue reached peak at 2 hours after dosing, decreasing steadily thereafter. Radioactivity in pig blood declined rapidly from 70 ng equivalents/g at 10 minutes to 1 ng equivalent/g or less by 28 days after administration of either AHTN or HHCB. Radioactivity in pig skin and adipose tissue decreased to below the limit of detection by 28 days for both the materials. Thin-layer chromatography showed multiple radioactive components in both species' urine after administration of either material. Components found in the urine of the 2 species were qualitatively similar but quantitatively different. Both AHTN and HHCB were completely metabolized and excreted. No unchanged parent compound was detected in rat or pig urine.
Asunto(s)
Benzopiranos/administración & dosificación , Tetrahidronaftalenos/administración & dosificación , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Administración Intravenosa , Animales , Benzopiranos/toxicidad , Benzopiranos/orina , Cromatografía en Capa Delgada , Heces/química , Femenino , Masculino , Perfumes/administración & dosificación , Perfumes/toxicidad , Ratas , Ratas Sprague-Dawley , Porcinos , Tetrahidronaftalenos/toxicidad , Tetrahidronaftalenos/orinaRESUMEN
The dopamine agonist rotigotine was developed for the treatment of Parkinson's disease and restless legs syndrome. Disposition, metabolism, elimination, and absolute bioavailability of rotigotine were determined in six healthy male subjects by using two different forms of administration in a randomized sequence with a crossover design. Treatment A (continuous infusion) consisted of a single radiolabeled 12-h intravenous infusion of 1.2 mg of rotigotine (0.6 mg of [(14)C] and 0.6 mg of unlabeled rotigotine, 3.7 MBq) solution. Treatment B (transdermal application) consisted of a single 10-cm(2) patch containing 4.5 mg of unlabeled rotigotine with a patch-on period of 24 h. During the 12 h-infusion, total radioactivity concentration rapidly increased within 2 h; there was a slight additional increase toward the end of infusion. Plasma concentrations of total radioactivity declined by 75% within 12 h after completion of infusion. More than 94% of the radioactivity was excreted 216 h after the start of infusion, 71% by the kidneys and 23% by feces. Renal elimination of the parent compound was <1%. Systemically absorbed rotigotine was rapidly metabolized. The major rotigotine biotransformation pathway was conjugation of the parent compound, mainly by sulfation; a second pathway was the formation of phase 1 metabolites (N-desalkylation) with subsequent conjugation. Plasma concentration-time profiles of unchanged rotigotine during and after infusion and during and after patch administration were comparable. Absolute bioavailability of transdermally applied rotigotine was 37%.
Asunto(s)
Absorción/efectos de los fármacos , Administración Cutánea , Agonistas de Dopamina/farmacocinética , Infusiones Intravenosas/métodos , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Absorción/fisiología , Adolescente , Adulto , Disponibilidad Biológica , Estudios Cruzados , Agonistas de Dopamina/sangre , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/orina , Humanos , Masculino , Persona de Mediana Edad , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/metabolismo , Tetrahidronaftalenos/orina , Tiofenos/sangre , Tiofenos/metabolismo , Tiofenos/orina , Adulto JovenRESUMEN
Disposition of lasofoxifene (LAS; 6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol. tartrate) was investigated in rats and monkeys after oral administration of a single oral dose of [(14)C]LAS. Total mean recoveries of the radiocarbon were 96.7 and 94.3% from rats and monkeys, respectively. The major route of excretion in both species was the feces, and based on a separate study in the bile duct-cannulated rat, this likely reflects excretion in bile rather than incomplete absorption. Whole-body autoradioluminography suggested that [(14)C]LAS radioequivalents distributed rapidly in the rat with most tissues achieving maximal concentrations at 1 h. Half-life of radioactivity was longest in the uvea (124 h) and shortest in the spleen ( approximately 3 h). LAS was extensively metabolized in both rats and monkeys because no unchanged drug was detected in urine and/or bile. Based on area under the curve((0-24)) values, >78% of the circulating radioactivity was due to the metabolites. A total of 22 metabolites were tentatively identified by liquid chromatography-tandem mass spectrometry. Based on the structures of the metabolites, six metabolic pathways of LAS were identified: hydroxylation at the tetraline ring, hydroxylation at the aromatic ring attached to tetraline, methylation of the catechol intermediates by catechol-O-methyl transferase, oxidation at the pyrrolidine ring, and direct conjugation with glucuronic acid and sulfuric acid. LAS and its glucuronide conjugate (M7) were the major circulating drug-related moieties in both rats and monkeys. However, there were notable species-related qualitative and quantitative differences in the metabolic profiles. The catechol (M21) and its sulfate conjugate (M10) were observed only in monkeys, whereas the glucuronide conjugate of the methylated catechol (M8) and hydroxy-LAS (M9) were detected only in rats.
Asunto(s)
Moduladores de los Receptores de Estrógeno/farmacocinética , Pirrolidinas/farmacocinética , Tetrahidronaftalenos/farmacocinética , Animales , Bilis/metabolismo , Cromatografía Líquida de Alta Presión , Moduladores de los Receptores de Estrógeno/sangre , Moduladores de los Receptores de Estrógeno/orina , Heces/química , Femenino , Macaca fascicularis , Masculino , Espectrometría de Masas/métodos , Pirrolidinas/sangre , Pirrolidinas/orina , Ratas , Ratas Sprague-Dawley , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/orina , Distribución TisularRESUMEN
The consumption of ponderosa pine (Pinus ponderosa), lodgepole pine (Pinus contorta), common juniper (Juniperus communis), and Monterey cypress (Cupressus macrocarpa) causes abortions in pregnant cattle. Recent studies have identified isocupressic acid (1) as the primary abortificient compound in these plants. In vitro and in vivo studies using rumen and blood have shown isocupressic acid (1) is rapidly metabolized to agathic acid (3), dihydroagathic acid (4), and tetrahydroagathic acid (5). Rapid and sensitive diagnostic techniques are needed to identify poisoned animals, to study toxicokinetics, and to elucidate the mechanism of isocupressic acid-induced abortion in cattle. In this study, four competitive inhibition enzyme-linked immunosorbent assays for isocupressic acid and its sera metabolites were developed using polyclonal antibodies. One assay is specific to 1, whereas the other three assays show cross-reactivity to 3-5 in addition to 1. The assay specific to 1 had a limit of detection of 44.1 pg. The other assays which demonstrated cross-reactivity to the isocupressic acid blood metabolites also had comparably low limits of detection. One assay was used to follow the absorption and elimination profile of isocupressic acid metabolites in both cow serum and urine after oral dosage of a cow with common juniper.
Asunto(s)
Ácidos Carboxílicos/análisis , Ácidos Carboxílicos/sangre , Diterpenos/análisis , Diterpenos/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Tetrahidronaftalenos/análisis , Tetrahidronaftalenos/sangre , Abortivos/análisis , Abortivos/sangre , Animales , Ácidos Carboxílicos/orina , Bovinos , Diterpenos/orina , Femenino , Juniperus/química , Pinus/química , Corteza de la Planta/química , Embarazo , Sensibilidad y Especificidad , Tetrahidronaftalenos/orinaRESUMEN
4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid (CAS 94497-51-5, Am-80) is a new synthetic retinoid which has been shown to have a potent topical antipsoriatic activity. Pharmaco-kinetic profiles of Am-80 were studied in dogs, mice and rabbits after percutaneous or subcutaneous administration of 14C-Am-80. Plasma protein binding of 14C-Am-80 was also studied in rats, dogs and humans. After topical application of 14C-labeled Am-80 by occlusive dressing technique at a dose of 1 mg 14C-Am-80/1,000 mg ointment/kg, the blood and plasma levels of radioactivity were below the detection limit in normal-skin dogs. In normal skin mice and rabbits, the plasma radioactivity peaked at 8 h (40.8 ng eq./ml) and at 12 h (34.0 ng eq./ml) after application, respectively. Percutaneous absorption of 14C-Am-80 was less than 2% of the dose for dogs, 34% for mice and 23% for rabbits. After subcutaneous administration at a dose of 1 mg/kg to mice, dogs and rabbits, plasma levels of radioactivity peaked at 1, 4 and 4 h after dosing with a concentration of 614.0, 902.9 and 757.7 ng eq./ml and then it declined with half-lives of 2.4, 7.2 and 4.1 h, respectively. Urinary and fecal excretion of radioactivity after subcutaneous administration at a dose of 1 mg/kg was 3.5 and 94.7% of the dose in dogs, 27.0 and 73.2% in mice and 43.5 and 45.6% in rabbits. A possible gastrointestinal secretion, which might lead to excretion into feces, was suggested from the results with bile-duct-cannulated dogs. Unchanged Am-80 was present in high amounts in the plasma and bile or feces of all animal species tested except in rat bile, in which Am-80 was predominantly detected in the form of its taurine conjugate (M-6). Hydroxylation of Am-80 to yield 7-hydroxy-Am-80 (M-4) and 6-hydroxy-Am-80 (M-3), which lead to the formation of 6-oxo-Am-80 (M-5), were commonly observed in all animal species. Taurine conjugation reaction of unchanged Am-80 and hydroxy-Am-80 (to form M-6 and both M-1 and M-2, respectively) was distinct in rats and dogs, but, hardly detected in mice and rabbits. The presence of tetrahydro-tetramethyl-naphtylamine (TTNA) was most marked in mice, followed by rabbits and rats, but it was almost absent in dogs. HPLC-RIA analysis of human samples obtained from the phase II and phase III clinical trials of Am-80 ointment suggested that fecal excretion was the major elimination route, and that hydroxylation and taurine conjugation reaction of unchanged and hydroxy-Am-80 also occurred. Unchanged Am-80 was predominant in human plasma as compared with metabolites M-1 to M-6. In vitro binding of 14C-Am-80 to the plasma protein was found to be more than 99% in rats, dogs and humans. In vivo plasma protein binding of 14C-Am-80 and/or its radioactive metabolites was also found to be more than 98% in rats and dogs after subcutaneous administration of 14C-Am-80. In both dogs and humans, in vitro. 14C-Am-80 appeared to be bound predominantly to serum albumin. The binding of 14C-Am-80 to human serum albumin was scarcely affected in the presence of diazepam, digitoxin or warfarin, indicating that there are no specific binding sites for Am-80 on serum albumin.
Asunto(s)
Benzoatos/farmacocinética , Retinoides/farmacocinética , Tetrahidronaftalenos/farmacocinética , Administración Tópica , Animales , Benzoatos/sangre , Benzoatos/orina , Biotransformación , Proteínas Sanguíneas/metabolismo , Perros , Femenino , Humanos , Inyecciones Subcutáneas , Absorción Intestinal , Masculino , Ratones , Ratones Endogámicos ICR , Pomadas , Unión Proteica , Conejos , Ratas , Ratas Sprague-Dawley , Retinoides/sangre , Retinoides/orina , Suspensiones , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/orinaRESUMEN
4-[(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbamoyl]benzoic acid (CAS 94497-51-5, Am-80) is a new synthetic retinoid which has been shown to have a potent topical antisporiatic activity. The accumulation characteristics of Am-80 were examined in rats after a single and consecutive subcutaneous administration of 14C-labeled Am-80 once a day for 24 days, at a daily dose of 0.2 mg/kg. As compared with the single administration, Tmax (1-2 h) and Cmax (about 50 ng eq./ml) of the blood radioactivity were not altered markedly after the consecutive administration. During the daily subcutaneous dosing, the blood level of radioactivity at 24 h after each dosing was also very low. These findings suggested that accumulation in the blood was low after long term consecutive administration of Am-80. The plasma levels of total radioactivity and the proportion of unchanged Am-80 to the total plasma radioactivity, being about 80% at 2 h after administration, and plasma elimination half-life of Am-80, being approximately 3 h, appeared to be hardly affected by the consecutive administration. The cumulative excretion of radioactivity at 168 h after the final dosing was 6.7% and 89.1% in the urine and feces, respectively. The radioactivity remaining in the carcass at this time was about 3% of the total dose. The excretion profile was not altered by the consecutive administration. In most tissues, the concentration of radioactivity at 24 h after each dose reached a steady-state within 24 doses. At 2 h after the consecutive administration for 24 days, the highest concentration of radioactivity was found in the liver followed by the adrenal gland. Accumulation and delayed elimination of radioactivity in most tissues, especially in the adrenal gland, fat, skin and epididymis, were evidently observed as predicted from the previous study where 14C-Am-80 was administered at a dose of 1 mg/kg. The profile of accumulation and retention of radioactivity after the consecutive administration may be considered as a common characteristic of retinoids, such as etretinate.
Asunto(s)
Benzoatos/farmacocinética , Retinoides/farmacocinética , Tetrahidronaftalenos/farmacocinética , Animales , Autorradiografía , Benzoatos/administración & dosificación , Benzoatos/orina , Heces/química , Semivida , Inyecciones Subcutáneas , Masculino , Ratas , Ratas Sprague-Dawley , Retinoides/administración & dosificación , Retinoides/orina , Absorción Cutánea , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/orina , Distribución TisularRESUMEN
The objective of the study was to develop a sensitive and specific assay for studying the pharmacokinetics of a novel calcium antagonist, a benzimidazolyl-substituted tetraline derivative, mibefradil (I) in the dog. The assay involves liquid-liquid extraction of a biological sample, reversed-phase HPLC separation and fluorescence detection (lambda ex = 270 nm and lambda em = 300 nm) of sample components. Each sample was eluted with a mobile phase pumping at a flow-rate of 2 ml/min. The mobile phase composition was a mixture of acetonitrile and aqueous solution (38:62, v/v). The aqueous solution contains 0.0393 M KH2PO4 and 0.0082 M Na-pentanesulphonic acid. The retention times were 10.7 min for I, and 12.2 min for internal standard Ro 40-6792. Calibration curves with concentrations of I ranging from 10 to 500 ng/ml were linear (r2 > 0.99). The detection limit for I was 0.5 ng/ml when 0.5 ml of plasma or urine was used. Intra- and inter-day accuracy and precision were within 10%. The assay was successfully applied to the pharmacokinetic studies of I in dogs.
Asunto(s)
Bencimidazoles/análisis , Bloqueadores de los Canales de Calcio/análisis , Cromatografía Líquida de Alta Presión/métodos , Tetrahidronaftalenos/análisis , Animales , Bencimidazoles/sangre , Bencimidazoles/farmacocinética , Bencimidazoles/orina , Bloqueadores de los Canales de Calcio/sangre , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/orina , Perros , Mibefradil , Estándares de Referencia , Reproducibilidad de los Resultados , Espectrometría de Fluorescencia , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/farmacocinética , Tetrahidronaftalenos/orinaRESUMEN
The parent compound and one metabolite have been isolated from urine of five healthy male volunteers who received a single 200 mg oral dose of DP-1904. These compounds were extracted by using a Sep-Pak C18 cartridge and purified by the preparative HPLC method. On the basis of proton magnetic resonance and mass spectral data, unchanged drug and its ester glucuronide have been identified in human urine. DP-1904 has one asymmetric carbon and is used as a racemate in the current clinical trial. The enantiomeric compositions of unchanged DP-1904 and aglycon of DP-1904 glucuronide were determined by HPLC with optical activity and ultraviolet detection. The (R)-(+)-enantiomer percentages in unchanged DP-1904 and aglycon of its ester glucuronide in human urine collected at 0-4 hr after oral dosing were 60 +/- 1.3% and 38 +/- 1.4% (mean +/- SE, n = 5), respectively. The 0-4 hr urine collection represented approximately 80% of the given dose. These studies demonstrate that DP-1904 undergoes stereoselective disposition in humans. However, the difference in urinary excretion between DP-1904 enantiomers was rather small.
Asunto(s)
Imidazoles/orina , Tetrahidronaftalenos/orina , Cromatografía Líquida de Alta Presión , Glucuronatos/orina , Humanos , Espectroscopía de Resonancia Magnética , Espectrofotometría Ultravioleta , EstereoisomerismoAsunto(s)
Dopaminérgicos/análisis , Naftalenos/análisis , Tetrahidronaftalenos/análisis , Tiofenos/análisis , Cromatografía Líquida de Alta Presión/instrumentación , Dopaminérgicos/sangre , Dopaminérgicos/orina , Humanos , Reproducibilidad de los Resultados , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/orina , Tiofenos/sangre , Tiofenos/orinaRESUMEN
The disposition of a new thromboxane synthetase inhibitor, 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (DP-1904) upon administration of a single 200-mg oral dose to normal Japanese volunteers was studied. DP-1904 proved to be rapidly absorbed from the gastrointestinal tract and converted to its ester glucuronide, which appeared in plasma within 30 min after dosing. The AUCs of DP-1904 and its ester glucuronide were 7.23 +/- 0.54 and 7.93 +/- 0.86 micrograms.h/ml (mean +/- S.E., n = 5), respectively. Both compounds were also eliminated very rapidly from the body (half-lives greater than 60 min). The primary route of elimination was renal, with 52.1 +/- 2.2 and 37.6 +/- 1.6% of the dose being excreted in the urine as the unchanged form and the glucuronide conjugate within 48 h, respectively. The cumulative fecal excretion rates of DP-1904 up to 48 h after dosing were approximately 0.5%. The main metabolite of DP-1904 in humans was DP-1904 glucuronide. Serum thromboxane (TX) B2 levels were reduced more than 98% within 1 h after dosing. There was still more than 75% suppression of serum TXB2 levels at 12 h after dosing. At 72 h TXB2 concentrations returned to control levels. These data indicate that DP-1904 is a potent and long-acting thromboxane synthetase inhibitor.
Asunto(s)
Imidazoles/farmacocinética , Naftalenos/farmacocinética , Tetrahidronaftalenos/farmacocinética , Tromboxano-A Sintasa/antagonistas & inhibidores , Adulto , Heces/análisis , Semivida , Humanos , Imidazoles/sangre , Imidazoles/orina , Masculino , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/orina , Tromboxano B2/sangreRESUMEN
1. The disposition and metabolic profiling of 2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin(I), a dopamine agonist, were studied in anaesthetized rats after i.v. administration and in non-anaesthetized rats after i.v. and oral dosing. No major differences due to narcosis were observed. 2. Independent of dosing route or anaesthetic, clearance of I was rapid. Bile was the main route of excretion, accounting for 88% dose, compared with 9% in urine. 3. Drug metabolic profiling revealed that I is almost completely metabolized before elimination; less than 0.5% total radioactivity in bile and urine was due to parent compound. 4. The biliary metabolic profiles after i.v. and oral administration were similar. One major metabolite was detected, accounting for 50% (i.v.) or 65% (oral) dose. The major biliary metabolite was identified as the glucuronide of I. 5. Urinary metabolic profiles were quantitatively different from those of bile. After i.v. administration one major metabolite was detected in urine, but this was not the major biliary metabolite. After oral administration, the major urine metabolite was the same as the major biliary metabolite. These differences can be explained by first-pass gastro-intestinal metabolism.
Asunto(s)
Dopaminérgicos/farmacocinética , Naftalenos/farmacocinética , Tetrahidronaftalenos/farmacocinética , Tiofenos/farmacocinética , Administración Oral , Anestesia , Animales , Bilis/metabolismo , Glucuronatos/metabolismo , Infusiones Intravenosas , Masculino , Ratas , Ratas Endogámicas , Tetrahidronaftalenos/administración & dosificación , Tetrahidronaftalenos/orina , Tiofenos/administración & dosificación , Tiofenos/orina , Distribución Tisular , TritioRESUMEN
N-0437 is a recently developed dopamine (D2) agonist, theoretically attractive in the therapy of Parkinson's disease and glaucoma. Since its high potency allows small doses of the compound in clinical use and as extensive metabolism occurs in animals, a highly sensitive assay method was required for drug-monitoring purposes. To this end we developed a radioreceptor assay (RRA), a sensitive tool for the assessment of the sample's (dopaminergic) bioactivity. The RRA is based on competition between N-0437 and its tritium-labeled analogue for binding to dopamine receptors. The assay has been optimized for the preparation of the receptor suspension and the incubation conditions. Direct application of the assay for biological samples was impossible because of matrix interferences. Therefore, a solid-phase extraction method was developed in which the combination of a polar Si column and dichloromethane as eluent resulted in an effective elimination of the interferences. Recoveries were better than 90 and 95% for plasma and urine, respectively, even at concentrations at the determination limit of the method (300 pg/ml). Relative standard deviations were less than 15%. Because RRAs are stereoselective, the method discriminates between active and inactive species.
Asunto(s)
Dopaminérgicos/análisis , Naftalenos/análisis , Tetrahidronaftalenos/análisis , Tiofenos/análisis , Animales , Bovinos , Dopaminérgicos/sangre , Dopaminérgicos/orina , Humanos , Concentración de Iones de Hidrógeno , Ensayo de Unión Radioligante , Temperatura , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/orina , Tiofenos/sangre , Tiofenos/orinaRESUMEN
A high-performance liquid chromatographic method for the determination of 6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride hemihydrate (DP-1904), a potent and long-acting thromboxane synthetase inhibitor, in human plasma and urine has been developed. DP-1904 and an internal standard were extracted from plasma and urine by means of a Sep-Pak C18 cartridge. The methanol eluate was evaporated and the residue was chromatographed on a reversed-phase column using tetrahydrofuran-0.5% potassium dihydrogen phosphate solution (pH 3.0) (1:16) as the mobile phase at a flow-rate of 1.2 ml/min. Ultraviolet detection at 240 nm resulted in limits of detection of 50 ng/ml for plasma and 1.0 microgram/ml for urine. The method showed satisfactory accuracy and precision. The method was applied to the determination of DP-1904 in plasma and urine samples from a normal human volunteer who had received a 200-mg oral dose of the drug. DP-1904 was rapidly absorbed from the gastrointestinal tract and had a half-life of ca. 30 min. The primary route of elimination was renal, with ca. 60% of the dose being excreted in the urine in the unchanged form within 48 h.
Asunto(s)
Imidazoles/análisis , Naftalenos/análisis , Tetrahidronaftalenos/análisis , Tromboxano-A Sintasa/antagonistas & inhibidores , Cromatografía Líquida de Alta Presión , Semivida , Humanos , Imidazoles/sangre , Imidazoles/farmacología , Imidazoles/orina , Masculino , Tetrahidronaftalenos/sangre , Tetrahidronaftalenos/farmacología , Tetrahidronaftalenos/orinaRESUMEN
The structures of three isomeric 1,2,3,4-tetrahydroxytetrahydronaphthalene metabolites of naphthalene have been confirmed by synthesis. Six isometric 1,2,3,4-tetrahydroxy-1,2,3,4-tetrahydronaphthalene structures occurring in for dl-pairs and two mesoforms have been synthesized. Five were synthesized by the action of osmium tetroxide on the cis- and trans-1,2-dihydrodiols and cis- and trans-1,4-dihydrodiols. The sixth isomeric tetrahydrotetrol was synthesized by hydrolysis of trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydronaphthalene (the syn-dihydrodiolepoxide of naphthalene). By comparing the gas-chromatographic and mass-spectrometric properties of the synthetic and urinary tetrahydrotetrols, two of the urinary metabolites were identified as 1 beta, 2 alpha, 3 alpha, 4 beta- and structure of the third tetrahydrotetrol metabolite, 1 beta, 2 alpha, 3 beta, 4 alpha-tetrahydroxy-1,2,3,4-tetrahydronaphthalene, identified in earlier studies, was confirmed.