RESUMEN
PURPOSE: To evaluate whether the impact of functional modulation of the breast cancer resistance protein (BCRP, ABCG2 421C>A) on human pharmacokinetics after oral administration is predictable using Bcrp knockout mice and cynomolgus monkeys pretreated with a BCRP inhibitor, elacridar. METHODS: The correlation of the changes of the area under the plasma concentration-time curve (AUC) caused by ABCG2 421C>A with those caused by the Bcrp knockout in mice, or BCRP inhibition in monkeys, was investigated using well-known BCRP substrates (rosuvastatin, pitavastatin, fluvastatin, and sulfasalazine). RESULTS: In mice, the bioavailability changes, which corrected the effect of systemic clearance by Bcrp knockout, correlated well with the AUC changes in humans, whereas the correlation was weak when AUC changes were directly compared. In monkeys, the AUC changes pretreated with elacridar resulted in a good estimation of those in humans within approximately 2-fold ranges. CONCLUSIONS: This study suggests that pharmacokinetics studies that use the correction of the bioavailability changes in Bcrp knockout mice are effective for estimating clinical AUC changes in ABCG2 421C>A variants for BCRP substrate drugs and those studies in monkeys that use a BCRP inhibitor serve for the assessment of BCRP impact on the gastrointestinal absorption in a non-rodent model.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Antiinflamatorios no Esteroideos/farmacocinética , Ácidos Grasos Monoinsaturados/farmacocinética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Indoles/farmacocinética , Quinolinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Sulfasalazina/farmacocinética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transportadoras de Casetes de Unión a ATP/metabolismo , Acridinas/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/sangre , Área Bajo la Curva , Células CACO-2 , Ácidos Grasos Monoinsaturados/administración & dosificación , Ácidos Grasos Monoinsaturados/sangre , Femenino , Fluvastatina , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/sangre , Indoles/administración & dosificación , Indoles/sangre , Absorción Intestinal/efectos de los fármacos , Macaca fascicularis , Masculino , Ratones Noqueados , Quinolinas/administración & dosificación , Quinolinas/sangre , Rosuvastatina Cálcica/administración & dosificación , Rosuvastatina Cálcica/sangre , Sulfasalazina/administración & dosificación , Sulfasalazina/sangre , Tetrahidroisoquinolinas/farmacologíaRESUMEN
To gain a better understanding of the metabolic stability and transport of pitavastatin (CAS 147526-32-7), a new and potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, experiments were conducted using human hepatocytes and oocytes of Xenopus laevis expressing human organic anion transporting polypeptide-2 (OATP2), respectively. Almost the entire radioactivity was from the unchanged substance or lactone form in human hepatocytes, and the cytochrome P450 (CYP)-mediated metabolism of pitavastatin was negligible. The results suggested that CYPs are not critically involved in determining the metabolic fate of pitavastatin. The hepatic uptake of pitavastatin reached saturation with a Km of 2.99 +/- 0.79 micromol/L. Also, the uptake of pitavastatin was mediated by OATP2 expressed in oocytes with a Km of 5.53 +/- 1.70 micromol/L. These results indicated that OATP2 plays a major role in the distribution of pitavastatin in liver. Furthermore, to elucidate the increase in the plasma concentration of pitavastatin in a clinical setting, the inhibitory effect of ciclosporin (cyclosporin A, CAS 59865-13-3) on the uptake of pitavastatin was examined. The uptake of pitavastatin was inhibited in the presence of cyclosporin A and the apparent IC50 value was 2.91 +/- 0.78 micromol/L. This result may at least partly explain the drug-drug interaction between pitavastatin and cyclosporin A. In conclusion, the characterization of transporters needs to be taken into account to avoid transporter-mediated drug-drug interaction.
Asunto(s)
Hepatocitos/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Quinolinas/farmacocinética , Animales , Biotransformación , Cromatografía Líquida de Alta Presión , Criopreservación , Ciclosporina/farmacología , Estradiol/metabolismo , Femenino , Humanos , Indicadores y Reactivos , Cinética , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Quinolinas/antagonistas & inhibidores , Xenopus laevisRESUMEN
Antisense oligonucleotides (AONs) that specifically target the genes of rat organic anion transporting polypeptide (oatp) subtypes were selected by using antisense in vitro selection (AIVS) and a conventional gene alignment program (GAP). When we incorporated several of our original 2'-O,4'-C-ethylene-bridged nucleic acid (ENA) residues into AONs, which were designed as gapmers containing a series of 2'-deoxynucleotides in the center, at both the 3' and 5' ends, the inhibitory activity of these oatp AONs was enhanced and their inhibition was mediated by RNase H cleavage. Moreover, these ENA AONs did not lose their oatp selectivity. These strategies of using AIVS and GAP to select AONs followed by incorporation of ENA residues were effective for synthesizing oatp subtype-specific AONs.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Etilenos/síntesis química , Nucleósidos/síntesis química , Oligonucleótidos Antisentido/síntesis química , Transportadores de Anión Orgánico Sodio-Independiente/antagonistas & inhibidores , Transportadores de Anión Orgánico/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Animales , Secuencia de Bases , Transporte Biológico/genética , Hidrocarburos Aromáticos con Puentes/metabolismo , Etilenos/metabolismo , Marcación de Gen/métodos , Riñón/química , Riñón/metabolismo , Hígado/química , Hígado/metabolismo , Datos de Secuencia Molecular , Nucleósidos/metabolismo , Oligonucleótidos Antisentido/metabolismo , Oocitos/metabolismo , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico Sodio-Independiente/genética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Proteínas de Transporte de Catión Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Ratas , Alineación de Secuencia/métodos , Tionucleótidos/síntesis química , Tionucleótidos/metabolismo , Xenopus laevisRESUMEN
To select antisense oligonucleotides (AONs) that specifically target the genes of rat organic anion transporting polypeptide (oatp) subtypes, in vitro selection and an alignment program were used. When we incorporated a couple of our original 2'-O,4'-C-ethylene nucleoside (ENA) residues into the AONs at both the 3' and 5' ends, the inhibitory activity of these oatp subtype-specific AONs was enhanced. This strategy of combining in vitro selection with the use of an alignment program as well as incorporating ENA residues, was effective in synthesizing oatp subtype-specific AONs.