RESUMEN
Radixin (RDX) is part of the ezrin-radixin-moesin (ERM) protein family. It functions as a membrane-cytoskeletal linker in actin-rich cell surface structures and is thought to be essential for cortical cytoskeleton organization, cell motility, adhesion, and proliferation. An increase in phosphorylated ERM in fibroblast-like synoviocytes contributes to rheumatoid arthritis (RA) synovial hyperplasia. We examined the genetic association between the RDX gene and RA in a Korean population. To identify the relationship between RDX gene polymorphisms and RA, we genotyped 2 single nucleotide polymorphisms (SNPs; rs11213326 and rs12575162) of RDX using a direct sequencing method in 296 RA patients and 493 control subjects. In this study, the 2 SNPs showed no association with RA disease susceptibility. However, further analysis based on clinical information of the RA patient group showed that the SNPs were associated with the erythrocyte sedimentation rate (ESR) in RA patients. These data suggest an association between RDX polymorphisms and the clinical features of RA patients, particularly the ESR.
Asunto(s)
Artritis Reumatoide/genética , Sedimentación Sanguínea , Proteínas del Citoesqueleto/genética , Estudios de Asociación Genética , Proteínas de la Membrana/genética , Adulto , Artritis Reumatoide/patología , Pueblo Asiatico , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población , República de CoreaRESUMEN
Eperisone is a centrally acting muscle relaxant widely used for the therapeutic treatment of spastic patients to relieve muscle stiffness and back pain. The objective of this study was to characterize the metabolic pathway involved in the biotransformation of eperisone mediated by human cytochrome P450 (CYP) enzymes. Eperisone was metabolized to seven metabolites via oxidation and carbonyl reduction in human liver microsome. Among them, M3 and M4 were found to be primary major metabolites which were generated by CYPs. The kinetics study with (-)-R- and (+)-S-eperisones revealed that CYPs-mediated hydroxylation did not have significant stereoselectivity for metabolic clearance of eperisone. Incubation with recombinant CYP isozyme, chemical inhibition assay, and immuno-inhibition assay showed that multiple CYPs were involved in M4 formation, but mainly CYP2J2 in M3 formation. In addition, intestinal microsomes metabolized eperisone to M3 and M4 via CYP2J2- and CYP3A4-mediated reactions, which are supposed to contribute to presystemic metabolism of eperisone.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Microsomas Hepáticos/metabolismo , Relajantes Musculares Centrales/metabolismo , Propiofenonas/metabolismo , Anticuerpos/farmacología , Biotransformación , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Cromatografía de Gases y Espectrometría de Masas , Humanos , Mucosa Intestinal/metabolismo , Isoenzimas/metabolismo , Cinética , Redes y Vías Metabólicas/fisiología , Microsomas Hepáticos/enzimología , Relajantes Musculares Centrales/química , Oxidación-Reducción , Propiofenonas/química , Proteínas RecombinantesRESUMEN
Pharmacokinetic and pharmacodynamic profiles of lorazepam and valproate were analyzed according to uridine 5'-diphosphate-glucuronosyltransferase (UGT)2B7 genotype in 14 healthy subjects with UGT2B15*2/*2 genotype. Systemic clearance of lorazepam (2 mg intravenously) and area under the concentration-time curve (AUC) of valproate (600 mg once daily for 4 days) were analyzed as pharmacokinetic parameters, and area under the effect-time curve (AUEC) of psychomotor coordination tests (Vienna) was used for pharmacodynamic parameter. No significant differences were found in systemic clearances of lorazepam by UGT2B7 genotype. AUCs of valproate showed an increasing tendency as the number of UGT2B7*2 alleles increased, but the difference was insignificant. Psychometric results were significant among the UGT2B7 genotype group (AUEC_tracking 261.5+/-298.9 in *1/*1, and 3,396.8+/-947 in *2/*2, P=0.047) when the two drugs were coadministered. Our study suggests that the UGT2B7 genotype probably affects lorazepam-valproate pharmacodynamic interaction, especially in subjects who have homovariant genotypes of UGT2B7 and UGT2B15, although the effects on the pharmacokinetics are less significant.
Asunto(s)
Anticonvulsivantes/farmacología , Glucuronosiltransferasa/genética , Lorazepam/farmacología , Polimorfismo Genético , Ácido Valproico/farmacología , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Anticonvulsivantes/farmacocinética , Área Bajo la Curva , Femenino , Humanos , Lorazepam/administración & dosificación , Lorazepam/sangre , Lorazepam/farmacocinética , Masculino , Psicometría , Desempeño Psicomotor/efectos de los fármacos , Ácido Valproico/administración & dosificación , Ácido Valproico/sangre , Ácido Valproico/farmacocinéticaRESUMEN
CYP2A6 is a major catalyst of nicotine metabolism to cotinine. Previously, we demonstrated that the interindividual difference in nicotine metabolism is related to a genetic polymorphism of the CYP2A6 gene in Japanese. To clarify the ethnic differences in nicotine metabolism and frequencies of CYP2A6 alleles, we studied nicotine metabolism and the CYP2A6 genotype in 209 Koreans. The cotinine/nicotine ratio of the plasma concentration 2 h after chewing one piece of nicotine gum was calculated as an index of nicotine metabolism. The genotypes of CYP2A6 gene (CYP2A6*1A, CYP2A6*1B, CYP2A6*2, CYP2A6*3, CYP2A6*4 and CYP2A6*5) were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism or allele specific (AS)-PCR. There were ethnic differences in the allele frequencies of CYP2A6*1A, CYP2A6*1B, CYP2A6*4 and CYP2A6*5 between Koreans (45.7%, 42.8%, 11.0% and 0.5%, respectively) and Japanese (42.4%, 37.5%, 20.1% and 0%, respectively, our previous data). Similar to the Japanese, no CYP2A6*2 and CYP2A6*3 alleles were found in Koreans. The homozygotes of the CYP2A6*4 allele (four subjects) were completely deficient in cotinine formation, being consistent with the data among Japanese. The heterozygotes of CYP2A6*4 tended to possess a lower metabolic ratio (CYP2A6*1A/CYP2A6*4, 4.79 +/- 3.17; CYP2A6*1B/CYP2A6*4, 7.43 +/- 4.97) than that in subjects without the allele (CYP2A6*1A/CYP2A6*1A, 7.42 +/- 6.56; CYP2A6*1A/CYP2A6*1B, 9.85 +/- 16.12; CYP2A6*1B/CYP2A6*1B, 11.33 +/- 9.33). The subjects who possess the CYP2A6*1B allele appeared to show higher capabilities of cotinine formation. It was confirmed that the interindividual difference in nicotine metabolism was closely related to the genetic polymorphism of CYP2A6. The probit plot of the metabolic ratios in Koreans (8.73 +/- 11.88) was shifted to a higher ratio than that in the Japanese (3.78 +/- 3.09). In each genotype group, the Korean subjects revealed significantly higher metabolic ratios than the Japanese subjects. The ethnic difference in cotinine formation might be due to environmental and/or diet factors as well as genetic factors.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/metabolismo , Nicotina/metabolismo , Polimorfismo Genético , Adulto , Alelos , Cotinina/sangre , Citocromo P-450 CYP2A6 , Femenino , Frecuencia de los Genes , Heterocigoto , Homocigoto , Humanos , Japón , Corea (Geográfico) , Masculino , Nicotina/sangreRESUMEN
Dihydropyrimidine dehydrogenase (DPD) is the major metabolic enzyme in the catabolism of 5-fluorouracil, and the activity in normal tissues shows a wide variation among individuals. Recent studies demonstrate the relevance of DPD in the pharmacokinetics, toxicity, and antitumor efficacy of 5-fluorouracil. We investigated the DPD activity in peripheral blood mononuclear cell form 114 healthy subjects in Korea. The DPD activities in healthy volunteers were shown to follow a unimodal distribution. The mean of the activity was 0.28 +/- 0.16 nmol/min/mg protein. A wide (13-fold) intersubject variability was observed (range, 0.06-0.80 nmol/min/mg protein), and, on average, DPD activity in women (0.26 +/- 0.14) was 13% lower than in men (0.30 +/- 0.16). These findings indicate that the activity of DPD in this study was higher than in reports of research with French and white American populations.
Asunto(s)
Pueblo Asiatico , Leucocitos Mononucleares/enzimología , Oxidorreductasas/sangre , Adulto , Antimetabolitos Antineoplásicos/farmacología , Dihidrouracilo Deshidrogenasa (NADP) , Femenino , Fluorouracilo/farmacología , Humanos , Corea (Geográfico) , Masculino , Oxidorreductasas/efectos de los fármacos , Valores de Referencia , Factores SexualesRESUMEN
OBJECTIVE: To assess the possible involvement of CYP2C19 in the metabolism of lansoprazole in vivo. METHODS: Sixteen male Korean subjects, who had been phenotyped as extensive metabolizers and poor metabolizers of S-mephenytoin 4'-hydroxylation polymorphism (n = 8 each) with racemic mephenytoin with use of the 8-hour urine analysis of 4'-hydroxymephenytoin, took an oral dose of 30 mg lansoprazole, and blood samples were collected up to 48 hours after dosing. Lansoprazole and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection. RESULTS: The mean lansoprazole area under the concentration-time curve (AUC), elimination half-life (t1/2), and apparent oral clearance (CLoral) were significantly (p < 0.001) greater, longer, and lower, respectively, in the poor metabolizer than in the extensive metabolizer group. The mean values for the AUC of hydroxylansoprazole and AUC ratio of hydroxylansoprazole to lansoprazole were significantly (p < 0.01 to p < 0.001) less in the poor metabolizer than in the extensive metabolizer group, whereas those for the AUC of lansoprazole sulfone and ratio of lansoprazole sulfone to lansoprazole were greater (p < 0.001) in the former than in the latter group. In addition, the log10 4'-hydroxymephenytoin excreted in urine correlated significantly (p < 0.01) with the CLoral of lansoprazole. CONCLUSIONS: These results suggest that the hydroxylation of lansoprazole cosegregates with the genetically determined S-mephenytoin 4'-hydroxylation (CYP2C19) polymorphism in the Korean subjects.
Asunto(s)
Anticonvulsivantes/farmacocinética , Hidrocarburo de Aril Hidroxilasas , Inhibidores Enzimáticos/farmacocinética , Mefenitoína/farmacocinética , Omeprazol/análogos & derivados , Polimorfismo Genético/genética , Inhibidores de la Bomba de Protones , 2-Piridinilmetilsulfinilbencimidazoles , Administración Oral , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/orina , Cromatografía Líquida de Alta Presión , Citocromo P-450 CYP2C19 , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/metabolismo , Humanos , Hidroxilación , Corea (Geográfico) , Lansoprazol , Masculino , Mefenitoína/administración & dosificación , Mefenitoína/orina , Oxigenasas de Función Mixta/metabolismo , Omeprazol/administración & dosificación , Omeprazol/farmacocinética , Omeprazol/orina , FenotipoRESUMEN
Thiopurine methyltransferase (TPMT) is the enzyme responsible for the S-methylation of thiopurine drugs. The enzyme, present in human red blood cells (RBC), is known to exhibit genetic polymorphism and interethnic differences in its activity have been demonstrated. We have studied the role of TPMT polymorphism in Koreans and compared enzyme activity between this and other ethnic groups. In a population of 360 unrelated healthy Korean subjects TPMT activity showed a large interindividual variation ranging from 3.2 to 22.9 nmol ml-1 packed RBC h-1 with a median value of 12.0 and mode of 11.0 nmol ml-1 packed RBC h-1. The enzyme activity was higher in male subjects than that in female (median values; 12.2 vs 11.2, 95% confidence interval of the difference; -2.1, 4.0 nmol ml-1 packed RBC h-1). All subjects had detectable TPMT activity, but contrary to previous reports in other ethnic groups, this was distributed unimodally. The median RBC TPMT activity was very similar to values found in Caucasian populations, higher than in Floridian blacks and lower than that of a Norwegian Saami population.
Asunto(s)
Eritrocitos/enzimología , Metiltransferasas/sangre , Adulto , Femenino , Humanos , Corea (Geográfico) , Masculino , Factores SexualesRESUMEN
We studied the metabolic disposition of imipramine by measuring imipramine and its metabolites in plasma and urine simultaneously after a single oral dose of 25 mg of imipramine hydrochloride administered to 16 healthy (three Japanese and 13 Korean) volunteers. Four of the subjects were poor metabolizers (PMs) of metoprolol but extensive metabolizers (EMs) of S-mephenytoin (PMML/EMMP), five subjects were EMs of metoprolol but PMs of S-mephenytoin (EMML/PMMP) and seven subjects were EMs of both metoprolol and S-mephenytoin (EMML/EMMP). The mean (+/- S.D.) oral clearances of imipramine were smaller in the PMML/EMMP group and the EMML/PMMP group than in the EMML/EMMP group, although a statistical difference (P < .05) was found only in the EMML/PMMP vs. the EMML/EMMP group. The mean area under the plasma concentration-time curve (AUC) of desipramine was 9 times greater (P < .01) in PMML/EMMP group, whereas the mean value was 0.6 times smaller (P < .05) in the EMML/PMMP group than in the EMML/EMMP group. The log10 metoprolol/alpha-hydroxymetoprolol ratio correlated positively with the AUC of desipramine (P < .01) and with the AUC ratio of desipramine/imipramine (P < .05) but negatively with the AUC ratio of 2-hydroxyimipramine/imipramine (P < .05). Log10 percent 4'-hydroxymephenytoin excreted in 8-hr urine correlated positively with the AUC of desipramine (P < .01) and with the AUC ratio of desipramine/imipramine (P < .01). The urinary excretions of imipramine and its metabolites also reflected the data derived from plasma samples in the three different phenotype-paired panels.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Sistema Enzimático del Citocromo P-450/fisiología , Imipramina/farmacocinética , Isoenzimas/fisiología , Mefenitoína/metabolismo , Metoprolol/metabolismo , Oxigenasas de Función Mixta/fisiología , Adulto , Pueblo Asiatico , Citocromo P-450 CYP2D6 , Remoción de Radical Alquila , Femenino , Humanos , Hidroxilación , Masculino , FenotipoRESUMEN
Two independent studies showed that the 5-hydroxylation, but not the sulfoxidation, of omeprazole is more rapid in extensive metabolizers (EMs) than in poor metabolizers (PMs) of S-mephenytoin. In Caucasian, Chinese, and Korean PMs, the mean oral clearances were similar and not significantly different (85, 73, and 59 ml h-1 kg-1, respectively). However, the geometric mean clearance in Caucasian EMs (950 ml h-1 kg-1) was higher than in both Chinese EMs (426 ml h-1 kg-1, p < 0.05) and Korean EMs (446 ml h-1 kg-1, p < 0.01). The incidence of PMs of S-mephenytoin is higher in Chinese (14.6%) and Koreans (12.6%) than in Swedish Caucasians (3.3%). Therefore, the proportion of heterozygous compared to homozygous EMs is higher in Orientals than in Caucasians. This might explain the higher clearance of omeprazole in Caucasian EMs compared to the clearance of omeprazole in Chinese and Korean EMs of S-mephenytoin.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Pueblo Asiatico , Omeprazol/metabolismo , Población Blanca , Pueblo Asiatico/genética , Citocromo P-450 CYP2C19 , Sistema Enzimático del Citocromo P-450/genética , Humanos , Oxigenasas de Función Mixta/genética , Fenotipo , Población Blanca/genéticaRESUMEN
To assess the relationship between blood pressure (BP) and serum insulin level in non-obese (body mass index (BMI) < or = 27 kg m-2), middle-aged (40-64 years of age) Japanese subjects with normal glucose tolerance, a three-phase study protocol was designed. First, the responses of plasma glucose and serum insulin to an oral glucose load were compared between 40 patients with untreated essential hypertension and 40 age-, sex- and BMI-matched normotensive control subjects. Second, the glucose and insulin responses to an i.v. glucose load were evaluated in 7 non-obese hypertensive, 7 non-obese normotensive and 7 obese hypertensive subjects. Third, BP and serum lipid profile were compared between 21 hyperinsulinaemic (serum insulin level (while fasting, after glucose loading, or both) > 2 SDs higher than the mean) and 21 age-, sex- and BMI-matched normoinsulinaemic subjects (serum insulin level within 1 SD of the mean). The glucose and insulin responses to the oral glucose load were comparable between the hypertensive and normotensive groups. Similarly, the glucose and insulin responses to the i.v. glucose load were comparable between the non-obese hypertensive and normotensive groups, whereas the mean AUCinsulin in the obese hypertensive group was significantly greater (p < 0.01) than that in either of the non-obese groups. The respective mean values for systolic and diastolic BPs did not differ between the hyperinsulinaemic and normoinsulinaemic groups. The mean serum triglyceride and HDL cholesterol concentrations were significantly higher (p < 0.01) and lower (p < 0.05), respectively, in the hyperinsuslinaemic than in the normoinsulinaemic group.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glucemia/metabolismo , Presión Sanguínea , Prueba de Tolerancia a la Glucosa , Hipertensión/fisiopatología , Insulina/sangre , Índice de Masa Corporal , Estudios de Casos y Controles , Estudios Transversales , Diástole , Femenino , Humanos , Hipertensión/sangre , Hipertensión/epidemiología , Insulina/metabolismo , Secreción de Insulina , Masculino , Persona de Mediana Edad , Valores de Referencia , SístoleRESUMEN
The role of the endothelium was evaluated in the relaxation of rat and guinea pig aortic rings induced by ascorbic acid. Ascorbic acid relaxed rat and guinea pig aortic rings that were previously contracted with submaximal dose of phenylephrine (PE), in a concentration dependent manner. Removal of the endothelium significantly reduced the sensitivity but not the magnitude of the response to ascorbic acid. Methylene blue, but not propranolol, blocked the endothelial augmentation of vascular relaxation to ascorbic acid. Vessels precontracted with potassium chloride (high K+) were also relaxed by ascorbic acid. Methylene blue also inhibited the response to ascorbic acid in the intact vessels precontracted with high K+. A23187 and acetylcholine, but not ADP, variably caused endothelium dependent component relaxation in guinea pigs, whereas all of these three probes constantly caused it. In Ca(2+)-free medium, Ca(2+)-induced contraction of high K(+)-depolarized rat aorta was inhibited by the presence of ascorbate, which was more pronounced in endothelium intact rings than in endothelium denuded ones. PE-induced contraction in the presence of different concentrations of ascorbate reduced both the sensitivity and the maximal contractile force in rat aorta. Ascorbic acid (0.125-32 mM) did not change the pH in the medium. From these findings, it is speculated that 1) receptor- and potential-operated Ca2+ channels may be modulated by ascorbate, 2) endothelium has a significant role in promoting relaxation induced by ascorbic acid.
Asunto(s)
Ácido Ascórbico/farmacología , Endotelio Vascular/fisiología , Vasodilatación/efectos de los fármacos , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Cobayas , Técnicas In Vitro , Masculino , Ratas , Ratas WistarRESUMEN
Omeprazole (OPZ) is a proton pump inhibitor in gastric parietal cells. A reversed-phase high-performance liquid chromatographic method was developed that enables concentrations of OPZ and its major metabolites, omeprazole sulphone (OPZ-SFN) and hydroxy-omeprazole (H-OPZ), to be determined simultaneously in plasma and that of H-OPZ in urine. To prevent decomposition of OPZ, all the processes (extraction, injection and elution) were carried out under alkaline conditions. Recoveries of the analytes and internal standard were greater than 93.1%. The intra- and inter-assay coefficients of variation were less than 9.1 and 6.4% for plasma samples and less than 2.9 and 3.9% for urine samples, respectively. The minimum determinable concentration (relative standard deviation 10-15%) was 10 ng/ml for all analytes in plasma and H-OPZ in urine samples. The clinical applicability of this assay method was evaluated by determining plasma concentration-and urinary excretion-time courses of the respective analyte(s) in four healthy volunteers after an oral dose of 20 mg of OPZ. The present assay is considered to be simple, precise and accurate and suitable for the study of the kinetic disposition and metabolism of OPZ, which is an extensively metabolized drug in the human liver.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Omeprazol/sangre , Omeprazol/orina , Adulto , Carbono , Resistencia a Medicamentos , Humanos , Hidróxidos , Hígado/metabolismo , Masculino , Omeprazol/metabolismo , PolímerosRESUMEN
To explore the relationship between omeprazole disposition and genetically determined S-mephenytoin 4'-hydroxylation phenotype status, we examined the kinetic variables of omeprazole and its two primary metabolites in plasma (5-hydroxyomeprazole and omeprazole sulfone) and the excretion profile of its principal metabolite in urine (5-hydroxyomeprazole) in eight extensive (EMs) and eight poor metabolizers (PMs) recruited from a Korean population. Each subject received a p.o. dose of 20 mg of omeprazole as an enteric-coated formulation, and blood and urine samples were collected up to 24 hr postdose. Omeprazole and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection. The mean omeprazole area under the concentration-time curve (AUC), elimination half-life (T1/2) and apparent p.o. clearance were significantly (P less than .001) greater, longer and lower, respectively, in PMs than in EMs. The mean peak concentration and AUC of 5-hydroxyomeprazole and AUC ratio of 5-hydroxyomeprazole to omeprazole were significantly (P less than .01 to .001) less in PMs than in EMs. The mean peak plasma concentration, AUC of omeprazole sulfone and ratio of omeprazole sulfone to omeprazole were greater (P less than .001) and T1/2 was longer (P less than .001) in PMs than in EMs. The mean cumulative urinary excretion of 5-hydroxyomeprazole up to 24 hr postdose was significantly (P less than .001) less in PMs than in EMs. In addition, the log10 4'-hydroxymephenytoin excreted in urine correlated significantly (P less than .01) with the apparent p.o. clearance of omeprazole and half-lives of omeprazole, 5-hydroxyomeprazole and omeprazole sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Mefenitoína/metabolismo , Omeprazol/farmacocinética , 2-Piridinilmetilsulfinilbencimidazoles , Administración Oral , Adulto , Humanos , Hidroxilación , Corea (Geográfico) , Masculino , Omeprazol/análogos & derivados , Omeprazol/sangre , Omeprazol/metabolismo , Omeprazol/orinaRESUMEN
We studied the genetically determined hydroxylation polymorphism of S-mephenytoin in a Korean population (N = 206) and the pharmacokinetics of diazepam and demethyldiazepam after an oral 8 mg dose of diazepam administered to the nine extensive metabolizers and eight poor metabolizers recruited from the population. The log10 percentage of 4-hydroxymephenytoin excreted in the urine 8 hours after administration showed a bimodal distribution with an antimode of 0.3. The frequency of occurrence of the poor metabolizers was 12.6% in the population. In the panel study of diazepam in relation to the mephenytoin phenotype, there was a significant correlation between the oral clearance of diazepam and log10 urinary excretion of 4-hydroxymephenytoin (rs = 0.777, p less than 0.01). The plasma half-life of diazepam in the poor metabolizers was longer than that in the extensive metabolizers (mean +/- SEM, 91.0 +/- 5.6 and 59.7 +/- 5.4 hours, p less than 0.005), and the poor metabolizers had the lower clearance of diazepam than the extensive metabolizers (9.4 +/- 0.5 and 17.0 +/- 1.4 ml/min, p less than 0.001). In addition, the plasma half-life of demethyldiazepam showed a statistically significant (p less than 0.001) difference between the extensive metabolizers (95.9 +/- 11.3 hours) and poor metabolizers (213.1 +/- 10.7 hours), and correlated with the log10 urinary excretion of 4-hydroxymephenytoin (rs = -0.615, p less than 0.01). The findings indicate that the Korean subjects have a greater incidence of poor metabolizer phenotype of mephenytoin hydroxylation compared with that reported from white subjects and that the metabolism of diazepam and demethyldiazepam is related to the genetically determined mephenytoin hydroxylation polymorphism in Korean subjects.
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Diazepam/farmacocinética , Mefenitoína/metabolismo , Oxigenasas de Función Mixta/metabolismo , Adulto , Pueblo Asiatico , Creatinina/orina , Diazepam/efectos adversos , Femenino , Humanos , Hidroxilación , Corea (Geográfico) , Masculino , Mefenitoína/efectos adversos , Mefenitoína/análogos & derivados , Mefenitoína/orina , Oxigenasas de Función Mixta/genética , Nordazepam/metabolismo , Fenotipo , Polimorfismo GenéticoRESUMEN
We examined the utility of the postdose 3-h plasma metabolic ratio (MR) as a phenotyping method for assessing genetically determined debrisoquine-type oxidation polymorphism after an oral dose of 100 mg of metoprolol tartrate administered to 402 unrelated, healthy, and native East Asian (218 Korean and 184 Japanese) subjects. All of them were phenotyped simultaneously with the reported MR employing urine samples collected during an 8-h postdose period. In the two populations, the distribution histograms and probit plots of log10plasma MRs derived from the metoprolol/alpha-hydroxymetoprolol concentration values indicated a large gap between the extensive and poor metabolizers who were phenotyped by the reported criteria of the 8-h urinary MR. There were statistically significant (p less than 0.001) correlations (rs = 0.688 and 0.810, respectively) between the postdose urinary and plasma MRs in the Korean and Japanese populations. Two poor metabolizers (one each included in the two racial groups) identified according to the 8-h urinary MR gave the greatest plasma MRs (i.e., 549.7 among the Koreans and 150.0 among the Japanese). The results suggest that the one-point, postdose 3-h plasma MR is also useful for the phenotyping purpose of oxidation pharmacogenetic polymorphism of metoprolol, a widely prescribed beta-adrenoceptor blocking drug.
Asunto(s)
Pueblo Asiatico , Metoprolol/sangre , Adolescente , Adulto , Cromatografía Líquida de Alta Presión , Debrisoquina , Femenino , Humanos , Japón , Corea (Geográfico) , Masculino , Metoprolol/análogos & derivados , Metoprolol/orina , Persona de Mediana Edad , Oxidación-Reducción , FenotipoRESUMEN
We examined metoprolol oxidation capacity in 218 unrelated, healthy Korean subjects using the 8 h urinary metabolic ratio (MR) of metoprolol to alpha-hydroxymetoprolol after an oral dose of 100 mg metoprolol tartrate. The results were compared with those from 295 Japanese and 107 mainland Chinese whose metoprolol oxidation capacities were assessed in a similar manner. The frequency of occurrence of poor metabolisers (PMs) was 0.5% (1/218) in the Korean, 0.7% (2/295) in the Japanese and 0% in the Chinese population. However, the respective mean (+/- s.d.) MRs (0.84 +/- 1.14 and 0.87 +/- 0.90) in the Korean and Japanese extensive metabolisers (EMs) were significantly (P less than 0.001) less than that in the Chinese EMs (2.81 +/- 2.35), and the mode of the distribution histogram and the probit plot of data for Chinese EMs were shifted to the right compared with those for Korean and Japanese EMs. The results indicate that Koreans, like Japanese and mainland Chinese, have a much lower frequency of the PM phenotype of debrisoquine/sparteine-type oxidation compared with that reported for Caucasian populations. Chinese EMs appear to have a lower capacity to metabolise metoprolol to alpha-hydroxymetoprolol compared with Korean or Japanese EMs.