RESUMEN
Whether the combined use of probe drugs for CYP3A4 and P-glycoprotein can clarify the relative contribution of these proteins to pharmacokinetic variability of a dual substrate like tacrolimus has never been assessed. Seventy renal recipients underwent simultaneous 8-h pharmacokinetic profiles for tacrolimus, the CYP3A4 probe midazolam, and the putative P-glycoprotein probe fexofenadine. Patients were genotyped for polymorphisms in CYP3A5, CYP3A4, ABCB1, ABCC2 and SLCO2B1, -1B1, and 1B3. Carriers of the ABCB1 2677G>A polymorphism displayed lower fexofenadine Cmax (-66%; P = 0.012) and a trend toward higher clearance (+157%; P = 0.078). Predictors of tacrolimus clearance were CYP3A5 genotype, midazolam clearance, hematocrit, weight, and age (R2 = 0.61). Fexofenadine pharmacokinetic parameters were not predictive of tacrolimus clearance. In conclusion, fexofenadine pharmacokinetics varied considerably between renal recipients but most of this variability remained unexplained, with only minor effects of genetic polymorphisms. Fexofenadine cannot be used to assess in vivo CYP3A4-P-glycoprotein interplay in tacrolimus-treated renal recipients.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Tacrolimus/metabolismo , Tacrolimus/farmacocinética , Terfenadina/análogos & derivados , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Citocromo P-450 CYP3A/genética , Femenino , Humanos , Trasplante de Riñón , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Midazolam/farmacocinética , Persona de Mediana Edad , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/genética , Terfenadina/metabolismo , Terfenadina/farmacocinética , Adulto JovenRESUMEN
Tacrolimus, a dual substrate of CYP3A4 and CYP3A5 has a narrow therapeutic index and is characterized by high between-subject variability in oral bioavailability. This study investigated the effects of the recently described CYP3A4*22 intron 6 C>T single nucleotide polymorphism on in vivo CYP3A4 activity as measured by midazolam (MDZ) clearance and tacrolimus pharmacokinetics in two cohorts of renal allograft recipients, taking into account the CYP3A5*1/*3 genotype and other determinants of drug disposition. In CYP3A5 non-expressers, the presence of one CYP3A4*22T-allele was associated with a 31.7-33.6% reduction in MDZ apparent oral clearance, reflecting reduced in vivo CYP3A4 activity. In addition, at ⩾12 months after transplantation, steady-state clearance of tacrolimus was 36.8% decreased compared with homozygous CYP3A4*22CC-wild type patients, leading to 50% lower dose requirements. Both concurrent observations in stable renal allograft recipients are consistent with a reduced in vivo CYP3A4 activity for the CYP3A4*22T-allele.
Asunto(s)
Citocromo P-450 CYP3A/genética , Midazolam/farmacocinética , Polimorfismo de Nucleótido Simple/genética , Alelos , Estudios Transversales , Femenino , Genotipo , Humanos , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Tacrolimus/farmacocinéticaRESUMEN
Tacrolimus is metabolized by CYP3A4 and CYP3A5 and is characterized by a narrow therapeutic index and highly variable pharmacokinetics. This cross-sectional study in 59 renal transplant patients investigated the relationship among in vivo CYP3A4 activity (assessed using midazolam as a drug probe), CYP3A5 genotype on the one hand, and tacrolimus pharmacokinetics on the other hand, taking into account other potential determinants of tacrolimus disposition. In vivo CYP3A4 activity and CYP3A5 genotype explain 56-59% of variability in tacrolimus dose requirements and clearance, contributing ~25 and 30%, respectively. Hematocrit explains an additional 4-14%. These data indicate that CYP3A4- and CYP3A5-mediated tacrolimus metabolisms are major determinants of tacrolimus disposition in vivo and explain a substantial part of the clinically observed high interindividual variability in tacrolimus pharmacokinetics. Furthermore, these data provide a potential basis for a comprehensive approach to predicting tacrolimus dose requirement in individual patients and hence provide a strategy to tailor immunosuppressive therapy in transplant recipients.
Asunto(s)
Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Hematócrito , Inmunosupresores/farmacocinética , Trasplante de Riñón/inmunología , Tacrolimus/farmacocinética , Estudios Transversales , Femenino , Genotipo , Humanos , Inmunosupresores/administración & dosificación , Modelos Lineales , Desequilibrio de Ligamiento/genética , Masculino , Midazolam/farmacocinética , Persona de Mediana Edad , Análisis Multivariante , Tacrolimus/administración & dosificaciónRESUMEN
In vitro studies have identified cyclosporine and tacrolimus as CYP3A inhibitors. In the current study in renal allograft recipients, we used intravenously and orally administered midazolam as a drug probe to assess whether the study drugs at doses that are generally used in clinical practice have differential effects on in vivo hepatic and first-pass CYP3A activities. Systemic and apparent oral midazolam clearance were 24% (269 ± 73 vs. 354 ± 102 ml/min, P = 0.022) and 31% (479 ± 190 vs. 688 ± 265 ml/min, P = 0.013), respectively, lower in cyclosporine-treated patients (n = 20) than in matched tacrolimus-treated patients (n = 20). The latter displayed midazolam clearances similar to those in two larger cohorts of nonmatched tacrolimus-treated patients (n = 58 and n = 80) and to those receiving a calcineurin inhibitor-free regimen (n = 6). This implies that in vivo hepatic and first-pass CYP3A activities are significantly lower in patients receiving cyclosporine than in those receiving tacrolimus, indicating that, at the doses generally used in clinical practice, cyclosporine is the stronger of the two with respect to CYP3A inhibition. This observation has important implications in the context of drug-drug interactions in transplant recipients.