RESUMEN
Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the V(max) for OATP1B1-mediated transport of E(2)17ß-G (estradiol 17ß-d-glucuronide) was decreased >60%, whereas K(m) values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (K(m) 13.1 ± 0.43 µM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC(50) values for inhibition of E(2)17ß-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients.
Asunto(s)
Fluorobencenos/metabolismo , Hipoglucemiantes/metabolismo , Hipoglucemiantes/farmacología , Transportadores de Anión Orgánico/antagonistas & inhibidores , Pirimidinas/metabolismo , Sulfonamidas/metabolismo , Administración Oral , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Estradiol/análogos & derivados , Estradiol/metabolismo , Células HEK293 , Humanos , Hipoglucemiantes/administración & dosificación , Cinética , Transportador 1 de Anión Orgánico Específico del Hígado , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Rosuvastatina Cálcica , Espectrometría de Masas en Tándem , TransfecciónRESUMEN
The low oral bioavailability of the HIV protease inhibitor (HPI) saquinavir is dramatically increased by coadministration of the HPI ritonavir. Because saquinavir and ritonavir are substrates and inhibitors of both the drug transporter P-glycoprotein (P-gp) and of the metabolizing enzyme CYP3A4, we wanted to sort out whether the ritonavir effect is primarily mediated by inhibition of CYP3A4 or P-gp or both. P-gp is known to limit the bioavailability, brain, testis, and fetal penetration of its substrates, so effective inhibition of P-gp by ritonavir in vivo might open up pharmacological sanctuary sites for saquinavir, with the potential of beneficial effects on therapy, but also of increased toxicity. In vitro, P-gp-mediated transport of saquinavir and ritonavir was only moderately inhibited by both HPIs compared with the potent P-gp inhibitor PSC833. When [(14)C]saquinavir was orally coadministered with a maximum tolerated dose of ritonavir to wild-type and P-gp-deficient mice, saquinavir bioavailability was dramatically increased in both strains, but P-gp still limited the oral bioavailability of saquinavir, and its penetration into brain and fetus. These data indicate that in vivo, ritonavir is a relatively poor P-gp inhibitor. The highly increased bioavailability of saquinavir because of ritonavir coadministration most likely results from reduced saquinavir metabolism. Importantly, our data indicate that it is unlikely that ritonavir coadministration will substantially affect the contribution of P-gp to pharmacological sanctuary sites such as brain, testis, and fetus. Thus, if one wanted to effectively open these sites for therapeutic purposes, more efficient P-gp inhibitors should be applied.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Encéfalo/metabolismo , Feto/metabolismo , Ritonavir/administración & dosificación , Saquinavir/administración & dosificación , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Línea Celular , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Feto/efectos de los fármacos , Humanos , Riñón/citología , Riñón/efectos de los fármacos , Riñón/metabolismo , Células LLC-PK1 , Hígado/efectos de los fármacos , Hígado/metabolismo , Intercambio Materno-Fetal/efectos de los fármacos , Ratones , Ratones Noqueados , Embarazo , Saquinavir/farmacocinética , Porcinos , TransfecciónAsunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Fármacos Anti-VIH/farmacología , Infecciones por VIH/metabolismo , Inhibidores de la Proteasa del VIH/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Animales , Fármacos Anti-VIH/uso terapéutico , Resistencia a Múltiples Medicamentos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Ratones , Ratones NoqueadosRESUMEN
It was recently shown that naturally occurring Mdr1a mutant fetuses of the CF-1 outbred mouse stock have no placental Mdr1a P-glycoprotein (P-gp) and that this absence is associated with increased sensitivity to avermectin, a teratogenic pesticide. To further define the role of placental drug-transporting P-gp in toxicological protection of the fetus, we used mice with a targeted disruption of the Mdr1a and Mdr1b genes. Mdr1a(+/-)/1b(+/-) females were mated with Mdr1a(+/-)/1b(+/-) males to obtain fetuses of 3 genotypes (Mdr1a(+/+)/1b(+/+), Mdr1a(+/-)/1b(+/-), and Mdr 1a(-/-)/1b(-/-)) in a single mother. Intravenous administration of the P-gp substrate drugs [(3)H]digoxin, [(14)C]saquinavir, or paclitaxel to pregnant dams revealed that 2.4-, 7-, or 16-fold more drug, respectively, entered the Mdr1a(-/-)/1b(-/-) fetuses than entered wild-type fetuses. Furthermore, placental P-gp activity could be completely inhibited by oral administration of the P-gp blockers PSC833 or GG918 to heterozygous mothers. Our findings imply that the placental drug-transporting P-gp is of great importance in limiting the fetal penetration of various potentially harmful or therapeutic compounds and demonstrate that this P-gp function can be abolished by pharmacological means. The latter principle could be applied clinically to improve pharmacotherapy of the unborn child.