RESUMEN
Cytochrome P450 (CYP) 2C enzymes contribute to the metabolism of about 30% of all drugs. Known polymorphisms of the respective enzymes and drug-drug interactions have a major impact on the efficacy and safety of some CYP2C substrate drugs. In vivo - in vitro correlations including prediction of the effect of such covariates requires quantitative information on enzyme kinetics. In this article there will be a summary of the values of the Michaelis-Menten constant (K(m)), the maximal velocity (V(max)) and the intrinsic clearance (Cl(int); V(max)/K(m)) for 84 substrates (100 reactions) reported to be mediated by CYP2C9 (variant enzymes CYP2C9.1, CYP2C9.2 and CYP2C9.3), CYP2C8 and/or CYP2C19. Particularly contradictory findings for the same reactions call for some standardization in the assessment of enzyme kinetics.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/farmacocinética , Variación Genética/genética , Oxigenasas de Función Mixta/genética , Oxigenasas de Función Mixta/farmacocinética , Hidrocarburo de Aril Hidroxilasas/normas , Citocromo P-450 CYP2C9 , Interacciones Farmacológicas/genética , Humanos , Oxigenasas de Función Mixta/normas , Polimorfismo Genético , Especificidad por Sustrato/genética , Vitamina K Epóxido ReductasasRESUMEN
This article introduces pharmacogenetics and pharmacogenomics in the context of pharmacotherapy in the pediatric ICU setting. As an independent discipline (if it can be considered as such), pediatric or developmental pharmacogenetics is essentially at a neonatal stage. Available pharmacokinetic data derived from studies of drugs that are largely dependent on a single CYP pathway for their elimination provide initial assessments of the developmental profile of that particular CYP isoform. Essentially then, pharmacogenetics in a pediatric context refers to the changes in phenotype that occur as a child grows and develops. Furthermore, the apparent drug biotransformation "phenotype" may be influenced by disease (infection), environmental factors (diet and environmental contaminants) and concurrent medications; however, drug response is a function of the complex interplay among genes involved in drug transport, drug biotransformation, receptors, and signal transduction processes, among others. Therefore, optimization of pediatric pharmacotherapy necessarily requires that developmental changes in each of these areas and not just drug biotransformation be investigated thoroughly before the promise of pharmacogenetics and pharmacogenomics for rational therapeutics can be realized in children.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Farmacogenética , Farmacocinética , Esteroide 16-alfa-Hidroxilasa , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP1A2/farmacocinética , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/farmacocinética , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Sistema Enzimático del Citocromo P-450/farmacocinética , Glucuronosiltransferasa/metabolismo , Humanos , Unidades de Cuidado Intensivo Pediátrico/organización & administración , Metiltransferasas/metabolismo , Oxigenasas de Función Mixta/metabolismo , Oxigenasas de Función Mixta/farmacocinética , Esteroide Hidroxilasas/metabolismo , Esteroide Hidroxilasas/farmacocinéticaRESUMEN
BACKGROUND/AIMS: The kinetics of omeprazole and its primary metabolites 5'-hydroxyomeprazole and omeprazole sulfone were studied in healthy volunteers to evaluate omeprazole as a probe drug for the S-mephenytoin hydroxylase (CYP2C19) polymorphism. The plasma metabolic ratio obtained from the concentrations of omeprazole plus omeprazole sulfone over 5'-hydroxyomeprazole was investigated. METHODS: The time course of the omeprazole metabolic ratio was studied in 14 extensive metabolizers, one intermediate, and five poor metabolizers of CYP2C19 after a 1-week administration of 40 mg/d omeprazole. The ratio was then determined in 187 randomly selected Caucasian hospital patients and analyzed according to liver disease and co-medication. RESULTS: Between 1 and 4 h after omeprazole intake, the volunteers phenotyped by the urinary S/R-mephenytoin ratio were reliably identified as extensive metabolizers and poor metabolizers by an omeprazole metabolic ratio-antimode of 12. This antimode remained valid in eight extensive metabolizers and one poor metabolizer, who were re-investigated with 60 mg omeprazole b.i.d. for one week. Among 30 patients without concomitant drug intake, only one poor metabolizer (3.3%) was identified by both the S/R-mephenytoin ratio and omeprazole metabolic ratio. However, 30 of 47 patients with liver disease and 20 of 110 co-medicated patients without liver disease had a ratio > 12. This highly exceeded the poor metabolizer frequency of 3-4% in Caucasians. CONCLUSIONS: Like other phenotypic tests, the omeprazole metabolic ratio appears to reflect CYP2C19 genotype reliably only in individuals without liver disease or co-medication. The omeprazole metabolic ratio may serve the double purpose of phenotyping for CYP2C19 and to individualize dosing in omeprazole-treated patients.
Asunto(s)
Antiulcerosos/farmacocinética , Hidrocarburo de Aril Hidroxilasas , Hepatopatías/metabolismo , Omeprazol/análogos & derivados , Omeprazol/farmacocinética , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Anticonvulsivantes/farmacocinética , Citocromo P-450 CYP2C19 , Sistema Enzimático del Citocromo P-450/farmacocinética , Femenino , Genotipo , Humanos , Hepatopatías/tratamiento farmacológico , Hepatopatías/genética , Masculino , Mefenitoína/farmacocinética , Persona de Mediana Edad , Oxigenasas de Función Mixta/farmacocinética , Úlcera Péptica/tratamiento farmacológico , Úlcera Péptica/genética , Úlcera Péptica/metabolismo , Fenotipo , Polimorfismo GenéticoRESUMEN
Over the past two decades, pharmacokinetic data have clearly demonstrated that development can markedly influence the absorption, distribution, excretion, and metabolism of xenobiotics. With respect to many of the processes that govern drug metabolism, the underlying pharmacogenetic determinants that may control either the affinity or the capacity of a drug or toxicant substrate for the enzymes responsible for its biotransformation appear to be altered as a function of development by mechanisms that are, for the most part, not well defined. Nonetheless, for many xenobiotics, the pharmacogenetic-developmental interface produces a "pattern" for drug metabolism that, when characterized, supports the pharmacokinetic properties (eg, drug clearance) reported for many agents across the pediatric age spectrum. With the exception of a few relatively well-characterized adverse drug effects (eg, toxicity of 6-mercaptopurine in patients with absent thiopurine methyltransferase activity, increased incidence of hepatotoxicity to valproic acid in young infants), the relationship of development and pharmacogenetics to enhanced toxicity risk from xenobiotic exposure is poorly defined. However, failure to adequately appreciate the pharmacokinetic consequences of the pharmacogenetic-developmental interface and to individualize therapy accordingly may lead to a clinically significant risk of drug therapy, namely, over- or underdosing.
Asunto(s)
Farmacogenética , Farmacología Clínica , Alcohol Deshidrogenasa/farmacocinética , Arilamina N-Acetiltransferasa/farmacocinética , Biotransformación , Niño , Preescolar , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP2E1 , Sistema Enzimático del Citocromo P-450/farmacocinética , Epóxido Hidrolasas/farmacocinética , Humanos , Lactante , Oxigenasas de Función Mixta/farmacocinética , Oxidorreductasas/farmacocinéticaRESUMEN
Recent findings about individual isoforms of the cytochromes P450 involved in the metabolism of phenytoin (PHT) and carbamazepine (CBZ) make prediction of inhibition-based interactions possible. PHT is eliminated principally by hydroxylation to p-HPPH, a reaction catalyzed primarily by CYP2C9 and secondarily by CYP2C19 (S-mephenytoin hydroxylase). The principle of isoform specificity (drugs metabolized by the same isoform should exhibit interactions with the same inhibitors) was applied to the interactions of PHT with 17 inhibitors using two probes for CYP2C9, S-warfarin and tolbutamide. Eleven of 17 interactions (sulfaphenazole, phenylbutazone, fluconazole, azapropazone, cotrimoxazole, propoxyphene, miconazole, amiodarone, disulfiram, metronidazole, and stiripentol) could be explained by inhibition of CYP2C9. The remaining interactions (felbamate, omeprazole, cimetidine, fluoxetine, imipramine, and diazepam) were attributed to inhibition of CYP2C19. For CBZ, studies utilizing chemical inhibitors, immunoinhibition, liver bank correlations, and expressed enzymes established that CYP3A4 is the main enzyme catalyzing formation of CBZ-10, 11-epoxide. This explains the pronounced interactions of CBZ with erythromycin, troleandomycin, and other macrolide antibiotics (clarithromycin, josamycin, flurythromycin, and ponsinomycin). Work is in progress to explain the interactions of CBZ with other inhibitors. The literature contains no other information on isoforms involved in the metabolism of other major antiepileptic drugs.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas , Carbamazepina/metabolismo , Sistema Enzimático del Citocromo P-450/farmacocinética , Fenitoína/metabolismo , Carbamazepina/farmacocinética , Carbamazepina/farmacología , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2D6 , Citocromo P-450 CYP2E1 , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Interacciones Farmacológicas , Humanos , Oxigenasas de Función Mixta/antagonistas & inhibidores , Oxigenasas de Función Mixta/farmacocinética , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/farmacocinética , Oxidorreductasas N-Desmetilantes/antagonistas & inhibidores , Oxidorreductasas N-Desmetilantes/farmacocinética , Preparaciones Farmacéuticas/metabolismo , Fenitoína/farmacocinética , Fenitoína/farmacologíaRESUMEN
Steady-state kinetic studies for the reaction of the flavocytochrome p-cresol methylhydroxylase with the reducing substrates (S) p-cresol, 4-ethylphenol, and their corresponding alpha-deuteriated analogues are presented. The results from these experiments and those from studies involving various reoxidizing substrates support the proposed apparent ping-pong mechanism. With phenazine methosulfate (PMS) as the reoxidant for studies at pH 7.6 and 6 or 25 degrees C, the isotope effects on kcat are lower than the intrinsic isotope effect. The values for D(kcat/KS) are equal to the intrinsic effect for p-cresol at 25 degrees C and for 4-ethylphenol at both 6 and 25 degrees C. However, the value for this steady-state parameter at 6 degrees C for p-cresol is lower than the intrinsic effect. The values for D(kcat/KPMS) are nearly equal to 1.0 under all conditions. In contrast, the steady-state kinetic analysis for the isolated flavoprotein subunit of p-cresol methylhydroxylase involving p-cresol and PMS as substrates indicates that a random-binding mechanism is operating. Additionally, several of the steady-state parameters yield values for the apparent intrinsic isotope effect for the flavoprotein. The results of stopped-flow kinetic studies are also reported. At pH 7.6 the intrinsic isotope effect (Dk2) for the reduction of the enzyme by 4-ethylphenol is 4.8-5.0 at 25 degrees C and 4.0 at 6 degrees C. This technique yields a value for Dk2 of 7.05 at 6 degrees C and pH 7.6 for p-cresol.(ABSTRACT TRUNCATED AT 250 WORDS)