RESUMEN
The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).
Asunto(s)
Sulfato de Atazanavir/efectos adversos , Glucuronosiltransferasa/antagonistas & inhibidores , Inhibidores de la Proteasa del VIH/efectos adversos , Hiperbilirrubinemia/inducido químicamente , Ictericia/inducido químicamente , Hígado/efectos de los fármacos , Farmacogenética/normas , Predisposición Genética a la Enfermedad , Genotipo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Hiperbilirrubinemia/enzimología , Hiperbilirrubinemia/genética , Ictericia/enzimología , Ictericia/genética , Hígado/enzimología , Fenotipo , Medición de Riesgo , Factores de RiesgoRESUMEN
Efforts to define the genetic architecture underlying variable statin response have met with limited success, possibly because previous studies were limited to effect based on a single dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 preselected variants. Two large biobanks were used to construct dose-response curves for 2,026 and 2,252 subjects on simvastatin and atorvastatin, respectively. Atorvastatin was more efficacious, was more potent, and demonstrated less interindividual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in subjects homozygous for the minor allele vs. 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand the genetic factors contributing to drug response.
Asunto(s)
Registros Electrónicos de Salud , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/genética , Algoritmos , Alelos , Atorvastatina , LDL-Colesterol/sangre , Estudios de Cohortes , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Genotipo , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/uso terapéutico , Humanos , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Lípidos/sangre , Fenotipo , Polimorfismo de Nucleótido Simple , Pirroles/administración & dosificación , Pirroles/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Simvastatina/administración & dosificación , Simvastatina/uso terapéuticoRESUMEN
It was hypothesized that cis-resveratrol glucuronidation contributes to a greater extent to in-vitro disposition of total resveratrol than previously assumed. To this end, the kinetic data for cis-resveratrol glucuronidation are reported. Glucuronidation assays were conducted in human liver and intestinal microsomes and in uridine diphosphate-glucuronosyltransferases (UGTs) UGT1A1, UGT1A6, UGT1A9, and UGT1A10. Kinetic parameters were estimated for the major cis-resveratrol-3-O-glucuronide (cis-R3G). Substrate inhibition was observed with apparent V(max), K(m) and K(i) of 6.1 +/- 0.3/27.2 +/- 1.2 nmol min(-1) mg(-1), 415 +/- 48.1/989.9 +/- 92.8 and 789.6 +/- 76.3/1012 +/- 55.9 microM in human intestinal microsomes (HIMs) and UGT1A6, respectively (estimate +/- standard error (SE)). Biphasic kinetics were observed in human liver microsomes (HLMs), while sigmoidal kinetics were seen in UGT1A9 (V(max) = 11.92 +/- 0.2 nmol min(-1) mg(-1); K(m) = 360 microM; n = 1.27 +/- 0.07). The 4'-O-glucuronide (cis-R4'G) exhibited atypical kinetics in HLM, HIM, UGT1A1, and UGT1A10. UGT1A9 catalysed cis-R4'G formation at high substrate concentrations (V(max) = 0.33 +/- 0.015 nmol min(-1) mg(-1); K(m) = 537.8 +/- 67.8 microM). In conclusion, although the rates of formation of cis-R3G in HLM and UGT1A9 were higher than those for trans-R3G, the contribution to total resveratrol disposition could not be determined fully due to atypical kinetics observed.