Interaction of CYP3A4 with the inhibitor cobicistat: Structural and mechanistic insights and comparison with ritonavir.

Cobicistat is a derivative of ritonavir marketed as a pharmacoenhancer for anti-HIV therapy. This study investigated the interaction of cobicistat with the target protein, drug-metabolizing cytochrome P450 3A4 (CYP3A4), at the molecular level using spectral, kinetic, functional, and structural approaches. It was found that, similar to ritonavir, cobicistat directly coordinates to the heme via the thiazole nitrogen but its affinity and the binding rate are 2-fold lower: 0.030 µM and 0.72 s-1, respectively. The newly determined 2.5 Å crystal structure of cobicistat-bound CYP3A4 suggests that these changes arise from the inability of cobicistat to H-bond to the active site S119 and establish multiple stabilizing contacts with the F-F' connecting fragment, which becomes disordered upon steric clashing with the bulky morpholine moiety. Nonetheless, cobicistat inhibits recombinant CYP3A4 as potently as ritonavir (IC50 of 0.24 µM vs 0.22 µM, respectively) due to strong ligation to the heme and formation of extensive hydrophobic/aromatic interactions via the phenyl side-groups. To get insights into the inhibitory mechanism, the K257 residue, known to be solely and irreversibly modified by the reactive ritonavir metabolite, was substituted with alanine. Neither this nor control K266A mutation changed the extent of time-dependent inhibition of CYP3A4 by cobicistat and ritonavir, suggesting the existence of alternative inactivation mechanism(s). More importantly, K257 was found to be functionally important and contributed to CYP3A4 allosterism, possibly by modulating protein-ligand interactions through conformational dynamics.

Insuficiencia suprarrenal iatrogénica por la interacción entre ritonavir y fluticasona inhalada. Revisión de la literatura / Iatrogenic adrenal insufficiency secondary to an interaction between ritonavir and inhaled fluticasone. A review of the literature

INTRODUCCIÓN: El tratamiento antirretroviral de alta eficacia ha incrementado la expectativa de vida en los pacientes con infección por el virus de inmunodeficiencia humana (VIH), lo que ha traído consigo un aumento de comorbilidades propias del envejecimiento de la población, como es el caso de la enfermedad pulmonar obstructiva crónica (EPOC). Todo esto conlleva la necesidad de utilizar un mayor número de medicamentos y un aumento en el riesgo de interacciones farmacológicas con los antirretrovirales, especialmente con los inhibidores de la proteasa. MÉTODOS: Describimos un caso de insuficiencia suprarrenal iatrogénica por interacción entre ritonavir y fluticasona inhalada en un paciente diagnosticado de infección por VIH y EPOC. Posteriormente realizamos una revisión de casos clínicos publicados en adultos en la literatura médica (Medline) hasta diciembre del 2012. RESULTADOS: En el periodo estudiado se identificaron 34 casos, con una media de edad de 48 años. La dosis promedio de ritonavir fue de 187 mg/día, mientras que la de fluticasona fue de 866 μg/día. El promedio de tiempo de la interacción entre el ritonavir y la fluticasona fue de 8 meses. En el 85% de los casos se retiró la fluticasona una vez hecho el diagnóstico de insuficiencia suprarrenal/síndrome de Cushing. El 90% de los pacientes presentó una resolución completa del cuadro clínico con la modificación del tratamiento. CONCLUSIÓN: En los pacientes en tratamiento antirretroviral con un inhibidor de la proteasa potenciado con ritonavir en los que sea preciso el uso de corticoides inhalados, la beclometasona sería la mejor opción terapéutica

INTRODUCTION: Highly effective antiretroviral treatment has improved the life expectancy of human immunodeficiency virus (HIV) infected patients, but has led to an increase in the comorbidities related to aging, such as the chronic obstructive pulmonary disease (COPD). All this implies the need for a greater number of drugs and an increasing risk of drugs interactions with antiretroviral treatment, particularly protease inhibitors. METHODS: We report a case of iatrogenic adrenal insufficiency interaction secondary to ritonavir and inhaled fluticasone in an HIV-infected patient with COPD. A review was made of the cases reported in adults in the medical literature (Medline) up to December 2012. RESULTS: A total of 34 cases were reported. The mean age was 48 years. The mean dose of ritonavir was 187 mg/day, while the fluticasone dose was 866 μg/day. The average time of the interaction between ritonavir and fluticasone was 8 months. In 85% of cases fluticasone was discontinued at the time of diagnosis of adrenal insufficiency/Cushing syndrome. Almost all (90%) patients had a complete resolution of the symptoms after changing the treatment. CONCLUSION: HIV-infected patients on antiretroviral therapy with protease inhibitor boosted with ritonavir which requires the use of inhaled corticosteroids, beclomethasone would be the best treatment option