RESUMEN
A new technique for investigating drug-protein binding was developed employing capillary electrophoresis (CE) coupled with tris(2,2'-bipyridyl) ruthenium(II) [Ru(bpy)(3) (2+)] electrochemiluminescence (ECL) (CE-ECL) detection after equilibrium dialysis. Three basic drugs, namely pridinol, procyclidine and its analogue trihexyphenidyl, were successfully separated by capillary zone electrophoresis with end-column Ru(bpy)(3) (2+) ECL detection. The relative drug binding to human serum albumin (HSA) for each single drug as well as for the three drugs binding simultaneously was calculated. It was found that the three antiparkinsonian drugs compete for the same binding site on HSA. This work demonstrated that Ru(bpy)(3) (2+) CE-ECL can be a suitable technique for studying drug-protein binding.
Asunto(s)
Antiparkinsonianos/análisis , Electroforesis Capilar/métodos , Mediciones Luminiscentes/métodos , Albúmina Sérica/metabolismo , Antiparkinsonianos/metabolismo , Unión Competitiva , Humanos , Compuestos Organometálicos/análisis , Compuestos Organometálicos/química , Piperidinas/análisis , Piperidinas/metabolismo , Prociclidina/análisis , Prociclidina/metabolismo , Unión Proteica , Albúmina Sérica/química , Trihexifenidilo/análisis , Trihexifenidilo/metabolismoRESUMEN
The goals of the present study were: (1) to investigate the binding properties of (R)- and (S)-procyclidine and two achiral derivatives of muscarinic M1, M2 and M4 receptor subtypes and (2) to identify the interactions which allow these receptors to discriminate between the two stereoisomers. (R)-Procyclidine showed a higher affinity for human neuroblastoma NB-OK 1 muscarinic M1 and rat striatum muscarinic M4 receptors, as compared to rat cardiac M2 receptors. (S)-Procyclidine had a 130-fold lower affinity than (R)-procyclidine for M1 and M4 receptors, and a 40-fold lower affinity for M2 receptors. Pyrrinol, the achiral diphenyl derivative with the cyclohexyl group of (S)-procyclidine replaced by a phenyl group, has an eight-fold lower affinity for M1 and M4 receptors, as compared to (R)-procyclidine, and a three-fold lower affinity for M2 receptors. Hexahydro-procyclidine, the corresponding achiral dicyclohexyl compound, had a 10- to 20-fold lower affinity than (R)-procyclidine for the three receptors. The increase in binding free energy, which is observed when the phenyl and cyclohexyl groups of procyclidine are separately replaced by cyclohexyl and phenyl groups, respectively, was additive in the case of M1, M2 and M4 receptors. This indicates that the muscarinic receptor stereoselectivity was based on the coexistence of two binding sites, one preferring a phenyl rather than cyclohexyl group and the second preferring a cyclohexyl rather than a phenyl group. In addition, there were also binding sites for the hydroxy moiety and the protonated amino group of the ligands. The greater affinity and stereoselectivity of M1 and M4 muscarinic receptors for (R)-procyclidine reflected the better fit of the cyclohexyl group of (R)-procyclidine to the subsite of M1 and M4 as compared to M2 receptors.
Asunto(s)
Prociclidina/metabolismo , Receptores Muscarínicos/metabolismo , Animales , Cuerpo Estriado/metabolismo , Humanos , Técnicas In Vitro , Cinética , Masculino , N-Metilescopolamina , Proteínas del Tejido Nervioso/metabolismo , Neuroblastoma/metabolismo , Ratas , Ratas Endogámicas , Derivados de Escopolamina/metabolismo , Estereoisomerismo , Células Tumorales Cultivadas/metabolismoRESUMEN
Two cases are described of chronic schizophrenic patients maintained on depot neuroleptics, who developed severe extrapyramidal symptoms following a period of heavy betel nut consumption. A mechanism for this effect is proposed based on the pharmacological antagonism of the anticholinergic agent, procyclidine, by the active alkaloid ingredient of the betel, arecoline.
Asunto(s)
Areca , Enfermedades de los Ganglios Basales/etiología , Plantas Medicinales , Prociclidina/efectos adversos , Pirrolidinas/efectos adversos , Antipsicóticos/uso terapéutico , Areca/metabolismo , Arecolina/efectos adversos , Enfermedades de los Ganglios Basales/prevención & control , Interacciones Farmacológicas , Quimioterapia Combinada , Humanos , India , Masculino , Persona de Mediana Edad , Plantas Medicinales/metabolismo , Prociclidina/metabolismo , Prociclidina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Viaje , Reino UnidoRESUMEN
1. The biotransformation of procyclidine in isolated hepatocytes, prepared from untreated and from phenobarbital-pretreated rats, is described. 2. Major metabolic pathways are ketone formation on carbon-4 and monohydroxylation in cis-4, trans-4 and (1R*, 3R*, 7S* (or R*))-trans-3 positions of the cyclohexyl ring. 3. Minor pathways consist of monohydroxylation in (1R*, 3S*, 7R*)- and (1R*, 3S*, 7S*)-cis-3 and vicinal diol formation in (1R*, 3R*, 4S*, 7R* (or S*))-cis-3, cis-4 and (1R*, 3S*, 4R*, 7S* (or R*))-trans-3, trans-4 positions of the cyclohexyl part of the molecule. 4. After phenobarbital treatment monohydroxylation in cis-4, trans-4 and trans-3 and vicinal diol formation in trans-3, trans-4 positions are significantly increased and the cis-4 to trans-3 ratio is reversed. 5. The hypothesis is made that the monohydroxylations in cis-3 and trans-3 represent an intermediate step in the formation of the dihydroxycyclohexyl metabolites, since this pathway is not observed in vivo. The hypothesis is supported by incubation experiments of synthetic monohydroxycyclohexyl derivates of procyclidine with isolated rat hepatocytes.
Asunto(s)
Hígado/metabolismo , Prociclidina/metabolismo , Pirrolidinas/metabolismo , Animales , Biotransformación , Cromatografía de Gases , Sistema Enzimático del Citocromo P-450/metabolismo , Hidroxilación , Técnicas In Vitro , Hígado/efectos de los fármacos , Masculino , Fenobarbital/farmacología , Ratas , Ratas EndogámicasRESUMEN
The pharmacokinetics and pharmacodynamics of procyclidine (10 mg) after oral and intravenous administration were studied in six healthy volunteers. Treatment order was randomised and the study was placebo-controlled and conducted blind. After oral dosing the mean peak plasma concentration was 116 ng/ml and mean bioavailability was 75%. After both oral and intravenous dosing the mean values for the volume of distribution, total body clearance and plasma elimination half-life of procyclidine were in the order of 1 l/kg, 68 ml/min and 12 h respectively. Autonomic effects were maximal within 0.5 h of intravenous administration and at about 1-2 h after oral dosing. Significant effects on pupil diameter, visual near point, salivary secretion and heart rate occurred after intravenous treatment and similar but less marked effects occurred after the oral dose. Significant autonomic effects were still detectable 12 h after both forms of treatment.
Asunto(s)
Prociclidina/metabolismo , Pirrolidinas/metabolismo , Administración Oral , Adulto , Disponibilidad Biológica , Método Doble Ciego , Femenino , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Inyecciones Intravenosas , Cinética , Masculino , Persona de Mediana Edad , Prociclidina/efectos adversos , Prociclidina/farmacología , Pupila/efectos de los fármacos , Distribución Aleatoria , Saliva/análisis , Factores SexualesRESUMEN
Procyclidine, 1-cyclohexyl-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, was incubated with the 9000g supernatant fraction of rat liver homogenates, fortified with a NADPH generating system. Three major metabolites were isolated from the incubation mixture. They were identified as 1-(cis-4-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(trans-4-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, and (1R*, 3R*, 7S(R?)*)-1-(trans-3-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl) -1-propanol. The latter has not been detected previously in rat urine and probably represents an intermediate metabolite.
Asunto(s)
Hígado/metabolismo , Prociclidina/metabolismo , Pirrolidinas/metabolismo , Animales , Biotransformación , Cromatografía de Gases , Cromatografía en Capa Delgada , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratas , Ratas EndogámicasRESUMEN
After intraperitoneal administration of procyclidine, eight metabolites were isolated from rat urine. They were identified as 1-(4-oxocyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(cis-4-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(trans-4-hydrocyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol , (1R,3R,4S,7R)- and (1R,3R,4S,7S)-1-(cis-3,cis-4-dihydroxycyclohexyl)-1-phenyl-3-(1-py rrolidinyl)- 1-propanol, (1R,3R,4R,7R)- and (1R,3R,4R,7S)-1-(cis-3,trans-4-dihydroxycyclohexyl)-1-phenyl- 3-(1-pyrrolidinyl)-1-propanol, and one of both (1R,3S,4R,7R)- or (1R,3S,4R,7S)- 1-(trans-3,trans-4-dihydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl )-1-propanol by comparative TLC, GLC-MS and 13C-NMR spectroscopy.
Asunto(s)
Prociclidina/metabolismo , Pirrolidinas/metabolismo , Animales , Cromatografía en Capa Delgada , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia Magnética , Masculino , Ratas , Ratas EndogámicasRESUMEN
After pretreatment of adult male Wistar rats with phenobarbital, a well-known cytochrome P-450 inductor, the liver microsomal cytochrome P-450 content increased significantly compared to that of control rats. At the same time the amount of procyclidine, metabolized by the 9000 g supernatant fraction of rat liver homogenate fortified with a NADPH generating system, increased significantly as well. However when related to the liver microsomal cytochrome P-450 content, the amount of metabolized procyclidine does not differ anymore between phenobarbital treated and control rats. Therefore phenobarbital induces the in vitro metabolism of procyclidine.