RESUMEN
BACKGROUND: The effects of ketamine on respiration, alone, or in combination with opioids, have not been completely clarified. Both stimulant and depressant effects have been reported, as well as attenuation of opioid-induced hypoventilation at the expense of increased oxygen consumption. These conflicting results might partly be due to dose-dependent mechanisms. We have, therefore, determined the ventilatory effects of ketamine, in combination with alfentanil, using infusions to different pseudo steady-state concentrations. METHODS: On two separate days, eight healthy male volunteers were given alfentanil as a continuous computer-controlled infusion, aiming at a plasma concentration of 50 ng x mL(-1). After reaching apparent steady-state for alfentanil, racemic ketamine or placebo was administered in a protocol randomised for the two days. On the ketamine days a computer-controlled infusion, aiming for escalating ketamine plasma concentrations of 50, 100 and 200 ng x mL(-1), was added to the alfentanil infusion. On the placebo days saline was added. Using a face-mask with an occlusion valve, respiratory parameters were measured during air-breathing and after 6 repetitive 30-s CO2 challenges. RESULTS: The alfentanil infusion induced hypoventilation by decreasing respiratory rate, while tidal volume and respiratory drive were unaffected. This hypoventilation was antagonised by ketamine in a concentration-dependent manner mainly through an increase in respiratory rate. The CO2 response was not affected by alfentanil or ketamine. CONCLUSION: In the dose range of interest for postoperative, intensive-care and pain-clinic settings, ketamine antagonises the resting hypoventilation induced by alfentanil.
Asunto(s)
Alfentanilo/antagonistas & inhibidores , Anestésicos Disociativos/farmacología , Anestésicos Intravenosos/antagonistas & inhibidores , Hipoventilación/prevención & control , Ketamina/farmacología , Antagonistas de Narcóticos/farmacología , Adulto , Alfentanilo/administración & dosificación , Alfentanilo/efectos adversos , Alfentanilo/sangre , Análisis de Varianza , Anestésicos Disociativos/administración & dosificación , Anestésicos Disociativos/sangre , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/efectos adversos , Anestésicos Intravenosos/sangre , Dióxido de Carbono/administración & dosificación , Relación Dosis-Respuesta a Droga , Humanos , Hipoventilación/inducido químicamente , Bombas de Infusión , Ketamina/administración & dosificación , Ketamina/sangre , Análisis de los Mínimos Cuadrados , Masculino , Antagonistas de Narcóticos/administración & dosificación , Antagonistas de Narcóticos/sangre , Consumo de Oxígeno/efectos de los fármacos , Placebos , Respiración/efectos de los fármacos , Volumen de Ventilación Pulmonar/efectos de los fármacosRESUMEN
Penciclovir is a drug active against herpes simplex viruses located in the epidermis basal layer. The aim of this study was to compare the suction blister technique and microdialysis as methods to measure the penciclovir concentration in the skin after a single dose (250 mg) of its prodrug, famciclovir. Suction blister fluid, microdialysates and plasma were sampled from 11 healthy volunteers for 5 h after famciclovir administration. Both the suction blister technique and microdialysis showed that penciclovir reaches the skin in concentrations sufficient to inhibit herpes virus replication. The maximum concentration in both suction blister fluid and in microdialysate was observed later than in plasma. The microdialysis concentration was decreased by cooling of the skin surface and by adrenaline-mediated vasoconstriction. The microdialysis recovery of penciclovir was studied with respect to the flow-rate of perfusion medium through the microdialysis probe. Microdialysis and the suction blister technique can be used to study the time-concentration profile of penciclovir in the skin and microdialysis allows a continuous sampling of the drug for a prolonged time after administration.
Asunto(s)
2-Aminopurina/análogos & derivados , Aciclovir/análogos & derivados , Antivirales/farmacocinética , Profármacos/farmacocinética , Piel/metabolismo , 2-Aminopurina/farmacocinética , Aciclovir/sangre , Aciclovir/metabolismo , Administración Oral , Adulto , Vesícula/metabolismo , Soluciones para Diálisis/metabolismo , Epinefrina/farmacología , Famciclovir , Femenino , Guanina , Humanos , Masculino , Microdiálisis/métodos , Piel/efectos de los fármacos , Temperatura , Factores de Tiempo , Distribución Tisular , Vasoconstrictores/farmacologíaRESUMEN
BACKGROUND: The metabolism of omeprazole includes hydroxylation catalyzed by CYP2C19 and, to a minor extent, sulfoxidation, presumably by CYP3A4. Sulfoxidation may be the predominant pathway in individuals devoid of the genetically determined CYP2C19 activity. Ketoconazole is a known CYP3A4 inhibitor in daily doses from 200 to 400 mg. In this study ketoconazole was used as a probe to investigate the extent to which CYP3A4 is involved in omeprazole metabolism in vivo. METHODS: A single oral 20 mg dose of omeprazole before and after four daily doses of 200, 100, or 50 mg ketoconazole was given to 10 healthy subjects, previously phenotyped as poor or extensive metabolizers of S-mephenytoin. Concentrations of omeprazole, 5-hydroxyomeprazole, omeprazole sulfone, and ketoconazole were analyzed with reversed-phase HPLC methods in plasma samples collected repeatedly for 12 hours after dosing. RESULTS: After intake of 20 mg omeprazole with 0, 50, 100, and 200 mg ketoconazole, mean values for omeprazole sulfone area under the plasma concentration versus time curve from 0 to 6 hours [AUC(0-6)] were 482, 206, 167, and < 100 nmol/L.hr in extensive metabolizers and 3160, 2430, 937, and 534 nmol/L.hr in poor metabolizers, respectively. Mean omeprazole AUC(0-6) increased from 1660 to 2265 nmol/L.hr in extensive metabolizers and from 7715 to 15319 nmol/L.hr in poor metabolizers after intake of 200 mg ketoconazole. CONCLUSIONS: An oral daily dose of 100 to 200 mg ketoconazole is sufficient to provide a marked inhibition of the formation of the omeprazole sulfone in both extensive and poor metabolizers and leads to a doubling of omeprazole levels in poor metabolizers, whereas 50 mg ketoconazole provides only partial inhibition. We concluded that CYP3A4 catalyzes the sulfoxidation of omeprazole and that this is the predominant metabolic pathway of omeprazole in poor metabolizers of S-mephenytoin.
Asunto(s)
Antiulcerosos/farmacocinética , Anticonvulsivantes/farmacocinética , Antifúngicos/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Cetoconazol/farmacología , Mefenitoína/farmacocinética , Oxigenasas de Función Mixta/metabolismo , Omeprazol/farmacocinética , Adulto , Anciano , Antiulcerosos/administración & dosificación , Anticonvulsivantes/administración & dosificación , Antifúngicos/administración & dosificación , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Femenino , Humanos , Cetoconazol/administración & dosificación , Masculino , Mefenitoína/administración & dosificación , Persona de Mediana Edad , Omeprazol/administración & dosificación , Oxidación-Reducción/efectos de los fármacos , Factores de TiempoRESUMEN
A single oral dose of omeprazole (20 mg) was given orally to 160 healthy Caucasian Swedish subjects and tested as a probe for CYP2C19. The study was nonrandomized and included seven subjects previously classified as poor metabolizers (PM) of S-mephenytoin. The ratio between the plasma concentrations of omeprazole and hydroxyomeprazole (metabolic ratio; MR) was determined by HPLC in a blood sample drawn 3 h after drug intake. In 17 subjects the test was repeated and the MRs of omeprazole on the two occasions were correlated (rs = 0.85; p < 0.0001). There was a significant correlation between the MR of omeprazole and the S/R mephenytoin ratio among 141 subjects, in whom both ratios were determined (rs = 0.63, p < 0.001). All seven PMs of S-mephenytoin had higher MRs of omeprazole (7.1-23.8) than extensive metabolizers (EM) (0.1-4.9). All 160 subjects and another 15 Caucasian Swedish PMs previously phenotyped with mephenytoin were analysed with respect to the presence of the CYP2C19m1 allele by PCR amplification of the intron 4/exon 5 junction followed by Sma I digestion. EMs heterozygous for the CYP2C19m1 gene had MRs of omeprazole and S/R ratios of mephenytoin that were higher than those of subjects who were homozygous for the wild-type allele (p = 0.0001). Nineteen of the 22 PMs were homozygous for the CYP2C19m1 gene. Three were heterozygous for this allele. Thus, 41 of the 44 alleles (93%) of PMs were defective CYP2C19m1. One of the remaining three PM alleles was subsequently found to contain the CYP2C19m2 mutation, which has earlier been shown to be associated with the PM phenotype in Oriental populations. In conclusion, the phenotype determined by omeprazole correlated with that of mephenytoin, and was in good agreement with the genotype.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Mefenitoína/metabolismo , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Omeprazol/metabolismo , 2-Piridinilmetilsulfinilbencimidazoles , Adulto , Alelos , Citocromo P-450 CYP2C19 , Femenino , Genotipo , Humanos , Hidroxilación , Masculino , Persona de Mediana Edad , Sondas Moleculares , Omeprazol/administración & dosificación , Omeprazol/análogos & derivados , Omeprazol/farmacocinética , Farmacogenética , Fenotipo , Suecia , Población Blanca/genéticaRESUMEN
1. Fourteen healthy Swedish Caucasian subjects were given 20 mg of omeprazole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S-mephenytoin, four heterozygous extensive metabolisers (hetEM) and five subjects with a very rapid metabolism (rapidEM). 2. After the first dose, the relative mean areas under the plasma concentration vs time curve (AUC) of omeprazole in rapidEM, hetEM and PM were 1:3.7:20 (all different, P < 0.001). A similar relation was seen in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentrations of hydroxyomeprazole were higher in EM than in PM confirming that the hydroxy, but not the sulphone metabolite, is formed by the S-mephenytoin hydroxylase (CYP2C19). After 8 days of treatment, the differences between groups were similar. 3. After both the first and the eighth doses, the omeprazole/hydroxyomeprazole plasma concentration ratio, determined 3 h after drug intake, correlated with the mephenytoin S/R ratio (rs = 0.94; P < 0.001; n = 14) suggesting that omeprazole might be used to phenotype for CYP2C19. 4. After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gastrin correlated significantly with the AUC of omeprazole in plasma (rs = 0.79; P < 0.01; n = 13).