RESUMO
Sorafenib was suggested to cause drug-drug interaction (DDI) with the common anticoagulant, warfarin based on published studies. The inhibition on CYP2C9 enzyme was thought to be the mechanism, but further studies are warranted. Thus, a mechanistic PBPK/PD model for warfarin enantiomers was developed to predict DDI potential with sorafenib, aiming at providing reference for the rational use of both drugs. PBPK models of warfarin enantiomers were constructed by Simcyp software. A mechanistic PK/PD model was built in NONMEM software. PBPK model of sorafenib was fitted via a top-down method. The final PBPK/PD model of warfarin enantiomers was verified and validated by different dosing regimens, ethnicities and genetic polymorphisms, and used to perform DDI simulations between warfarin racemate and sorafenib among general populations and sub-populations with various CYP2C9 and VKORC1 genotypes. Results suggested low DDI risk between warfarin and sorafenib for general populations. Potentially serious consequence was seen for those carrying both CYP2C9 ∗2 and ∗3 and VKORC1 A/A genotypes. This PBPK/PD modeling approach for warfarin enantiomers enabled DDI evaluation with sorafenib. Close monitoring and warfarin dosage adjustment were recommended for patients carrying mutant genotypes. The novel model could be applied to investigate other drugs that may interact with warfarin.
Assuntos
Coagulação Sanguínea , Citocromo P-450 CYP2C9/genética , Interações Medicamentosas/fisiologia , Hemorragia , Sorafenibe , Vitamina K Epóxido Redutases/genética , Varfarina , Anticoagulantes/metabolismo , Anticoagulantes/farmacocinética , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Simulação por Computador , Relação Dose-Resposta a Droga , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Humanos , Coeficiente Internacional Normatizado , Modelos Biológicos , Modelos Teóricos , Testes Farmacogenômicos/métodos , Medição de Risco/métodos , Sorafenibe/metabolismo , Sorafenibe/farmacocinética , Varfarina/metabolismo , Varfarina/farmacocinéticaRESUMO
In the present study the in vitro antimicrobial activity, along with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), of different extracts of leaves of Mesua nagassarium were evaluated against 13 pathogenic microorganisms. The methanol extract and its pet-ether and carbon tetrachloride soluble fractions showed the highest antimicrobial activity. The carbon tetrachloride soluble fraction showed the maximum inhibition zone of 24.33 mm against Bacillus megaterium with MIC and MBC values of 7.81 ug/ml and 250 ug/ml, respectively. Ciprofloxacin (30 ug/disc) was used as standard antimicrobial agent. In the Brine shrimp lethality bioassay, the crude methanol extract and its carbon tetrachloride soluble fraction showed significant cytotoxicity with LC50 of 2.99 and 1.74 ug/ml, respectively as compared vincristine sulphate (LC50 value 0.543 ug/ml).
En el presente estudio se evaluó la actividad antimicrobiana in vitro, incluyendo la concentración inhibitoria mínima (CIM) y la concentración bactericida mínima (CBM), de diferentes extractos obtenidos de hojas de Mesua nagassarium en 13 microorganismos patógenos. El extracto metanólico y sus fracciones solubles en éter de petróleo y tetracloruro de carbono, mostraron la mayor actividad antimicrobiana. La fracción de compuestos solubles en tetracloruro de carbono mostró la zona de inhibición máxima de 24.33 mm en Bacillus megaterium con valores de CIM y and CBM de 7.81 ug/ml y 250 ug/ml, respectivamente. Como agente antimicrobiano estándar se utilizó ciprofloxacina (30 ug/disco). En el bioensayo de mortalidad de Brine shrimp el extracto metanólico y su fracción soluble en tetracloruro de carbono mostraron importante citotoxicidad con CL50 de 2.99 y 1.74 ug/ml, respectivamente, comparadas con el sulfato de vincristina (CL50 0.543 ug/ml).