RESUMEN
AIM: To investigate the effects of CYP3A4 and CYP2C8 enzymes on repaglinide's pharmacokinetics in healthy Malaysian subjects. METHODS: Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles. RESULTS: The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide's blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide's pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide. CONCLUSION: Genetic polymorphisms of CYP3A4, specifically CYP3A4*18, play a major role in contributing to the interindividual variability in repaglinide's pharmacokinetics.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Carbamatos/farmacocinética , Citocromo P-450 CYP3A/genética , Piperidinas/farmacocinética , Polimorfismo Genético , Adolescente , Adulto , Hidrocarburo de Aril Hidroxilasas/sangre , Pueblo Asiatico , Carbamatos/administración & dosificación , Carbamatos/sangre , Carbamatos/farmacología , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A/sangre , Genotipo , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/sangre , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Persona de Mediana Edad , Piperidinas/administración & dosificación , Piperidinas/sangre , Piperidinas/farmacología , Adulto JovenRESUMEN
OBJECTIVE: To estimate population pharmacokinetic parameters of repaglinide in 121 healthy Malaysian volunteers. METHODS: Each subject received 4 mg of oral repaglinide. Six blood samples were taken per individual (0, 30, 60, 120, 180 and 240 min) for repaglinide's serum concentration determination by using high-performance liquid chromatography. The parametric Iterative Two-Stage Bayesian Population Model (it2b) program followed by the Non-Parametric Adaptive Grid (npag) program was used to determine a population pharmacokinetic modelling of repaglinide. RESULTS: Using the npag program, the mean elimination rate constant (k(el)) of repaglinide was 0.58 +/- 0.27 h and the volume of distribution (V(d)) was 23.09 +/- 9.19 L/h. CONCLUSION: In this first report, specifically on the population pharmacokinetic modelling of repaglinide, the data generated should help us to better understand appropriate dosage-regimens for the drug.
Asunto(s)
Algoritmos , Carbamatos/farmacocinética , Hipoglucemiantes/farmacocinética , Piperidinas/farmacocinética , Adolescente , Adulto , Índice de Masa Corporal , Carbamatos/sangre , Femenino , Semivida , Humanos , Hipoglucemiantes/sangre , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Modelos Biológicos , Piperidinas/sangre , Adulto JovenRESUMEN
BACKGROUND: Cytochrome P450 3A4 (CYP3A4) is the major cytochrome involved in metabolizing of >60% of all drugs used in humans. A number of allelic variations in CYP3A4 gene are known to affect catalytic activity including CYP3A4*4, CYP3A4*5 and CYP3A4*18. We investigated the frequencies of CYP3A4*4, CYP3A4*5 and CYP3A4*18 alleles in a Malaysian population. This will impact treatment of patients receiving drugs metabolized by these alleles. METHODS: The study was conducted in 121 healthy Malaysian volunteers. DNA was extracted from leucocytes and the 3 alleles were determined by PCR-RFLP. The PCR product was later digested with restriction enzymes BstMA I, BshV I and Hpa II. RESULTS: No mutations were detected for CYP3A4*4 and CYP3A4*5 alleles. The frequency of the CYP3A4*18 allele in the Malaysian population is 2.1%. All 5 subjects with CYP3A4*18 mutations were found to be heterozygous. CONCLUSION: The present study describes polymorphisms of CYP3A4 among Malaysian subjects. Clinical relevance of these genetic variants in these healthy volunteers is under investigation.