Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes

Tacrolimus (TAC), a immunosuppressive drug used in solid organ transplantation, is metabolized by CYP3A4 and 3A5. The simultaneous administration of TAC and meropenem (MEP) in pediatric kidney transplant patients may led to a significant increase in plasma concentrations of TAC. We hypothesized that this negative pharmacokinetic interaction is due to the inhibition of the CYP3A4-mediated biotransformation of TAC by MEP, particularly in those individuals lacking the expression of CYP3A5. The aim of this study was to evaluate in vitro the potential metabolic interaction between TAC and MEP. Human liver microsomes were prepared with discard liver samples obtained from healthy donors (n=2) and individuals subjected to tumor resection (n=2). The specific CYP3A-dependent enzyme activity, testosterone 6-beta hydroxylase, was assayed in the absence (control) and in presence of TAC (5 and 20 µM), MEP (10 µM) and the combinations of TAC and MEP. TAC, incubated at 5 and 20 µM, inhibited (p<0.05) the CYP3A-mediated 6-beta hydroxylation of testosterone (18±13% and 51±16%, respectively). This finding may confirm the high affinity of CYP3A4 for TAC. MEP, at 10 µM, did not affect this enzyme reaction. After co-incubations of TAC and MEP, testosterone 6-beta hydroxylase activities resembled those observed when TAC was incubated alone. In control assays, rates of TAC metabolism were 30±20 and 120±40 pmol/min.mg of microsomal protein, respectively. MEP, at 10 µM, significantly inhibited (p<0.05) the hepatic biotransformation of TAC; rates (pmol/min.mg) of TAC metabolism (at 5 and 20 µM) were 20±10 (43±24% inhibition) and 70±50 (49±23% inhibition), respectively. These preliminary results show a metabolic interaction between TAC and MRP on CYP3A-dependent metabolism in human liver. The enhancement of the systemic availability of TAC observed in vivo in the co-administration with MEP would be due to the inhibition of the CYP3A4-dependent biotransformation of the immunosuppressive drug.Fil: Riva, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Molina, Manuel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Larsen, Karen Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Trezeguet Renatti, Guido. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Caceres Guido, Paulo Arturo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Bressan, Ignacio Guillermo. Hospital Italiano; ArgentinaFil: Licciardone, Nieves. Hospital Italiano; ArgentinaFil: Monteverde, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaLXVI Reunión anual de la Sociedad Argentina de Investigación Clínica; LXIX Reunión anual de la Sociedad Argentina de Immunología; LIII Reunión anual de la Asociación Argentina de Farmacología Experimental y XI Reunión anual de la Asociación Argentina de NanomedicinasArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaAsociación Argentina de Farmacología ExperimentalAsociación Argentina de Nanomedicina

Population pharmacokinetics of sublingually administered tacrolimus in infants and young children with liver transplantation

Aims: Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post-transplantation. Methods: Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense-sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. Results: Disposition of tacrolimus was best characterized by a 2-compartment model with clearance achieving half of the maximum elimination capacity (CLMAX = 4.1 L/h) at 4.6 days post-transplantation (T50). Compared to sedated patients, nonsedated status showed an increased first-order absorption rate constant (1.1 vs. 0.1 h−1) and a 24% reduction in bioavailability (FNS) at 14 days post-transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first-pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T50). Conclusion: A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post-transplant time on clearance and the sedation status may be considered in routine dosing management.Fil: Riva, Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ibarra, Manuel. Universidad de la Republica; UruguayFil: Parra Guillen, Zinnia P.. Universidad de Navarra; EspañaFil: Galván, Maria Eugenia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Pérez, Erika. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Trezeguet Renatti, Guido. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Cáceres Guido, Paulo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Lopez, Clarisa. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Licciardone, Nieves. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Halac, Esteban Tomas. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Dip, Marcelo Fabian. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Cruz, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Imventarza, Oscar Cesar. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Buamscha, Daniel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Troconiz, Iñaki F.. Universidad de Navarra; EspañaFil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentin