An evaluation of potential mechanism‐based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid

Abstract

AimsTo characterize potential mechanism-based inactivation (MBI) of major human drugmetabolizing cytochromes P450 (CYP) by monoamine oxidase (MAO) inhibitors, including the antitubercular drug isoniazid. MethodsHuman liver microsomal CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A activities were investigated following co-and preincubation with MAO inhibitors. Inactivation kinetic constants ( K I and k inact ) were determined where a significant preincubation effect was observed. Spectral studies were conducted to elucidate the mechanisms of inactivation. ResultsHydrazine MAO inhibitors generally exhibited greater inhibition of CYP following preincubation, whereas this was less frequent for the proparg ylamines, and tranylcypromine and moclobemide. Phenelzine and isoniazid inactivated all CYP but were most potent toward CYP3A and CYP2C19. Respective inactivation kinetic constants ( K I and k inact ) for isoniazid were 48.6 µ M and 0.042 min − 1 and 79.3 µ M and 0.039 min − 1 . Clorgyline was a selective inactivator of CYP1A2 (6.8 µ M and 0.15 min − 1 ). Inactivation of CYP was irreversible, consistent with metabolite-intermediate complexation for isoniazid and clorgyline, and haeme destruction for phenelzine. With the exception of phenelzine-mediated CYP3A inactivation, glutathione and superoxide dismutase failed to protect CYP from inactivation by isoniazid and phenelzine. Glutathione partially slowed (17%) the inactivation of CYP1A2 by clorgyline. Alternate substrates or inhibitors generally protected against CYP inactivation. ConclusionsThese data are consistent with mechanism-based inactivation of human drugmetabolizing CYP enzymes and suggest that impaired metabolic clearance may contribute to clinical drug-drug interactions with some MAO inhibitors. CYP inactivation by MAO inhibitorsBr J Clin Pharmacol 61 :5 571

Effect of Albumin on Human Liver Microsomal and Recombinant CYP1A2 Activities: Impact on In Vitro-In Vivo Extrapolation of Drug Clearance

“…In the absence of BSA, the respective K m values of the high-affinity component of PHEN O-deethylation by HLM and rCYP1A2 (11.4 -67.8 and 13.6 M) were similar to previously published ranges (9 -38.4 and 12.3-30.9 M) (Gillam and Reilly, 1988;Tassaneeyakul et al, 1993;Venkatakrishnan et al, 1998;Kobayashi et al, 1999;Polasek et al, 2006b;Donato et al, 2010). Likewise, K m values of the high-affinity component of LID N-deethylation by HLM (135-246 M) were similar to data reported by Wang et al (2000).…”

Simple, Direct, and Informative Method for the Assessment of CYP2C19 Enzyme Inactivation Kinetics

“…For that reason, the probe substrate at the concentration corresponding to its measured apparent K m (data not shown) was used in the experiments, and this was taken into account when kinetic constants of the inactivation were determined. The inactivation kinetic constants (K I and k inact ) determined for isoniazid and ticlopidine correlated with published data (Wen et al, 2002;Nishimura et al, 2003;Polasek et al, 2006;Kalgutkar et al, 2007;Venkatakrishnan and Obach, 2007;Nishiya et al, 2009).…”

Un diagnóstico no pensado: toxicidad serotoninérgica secundaria a interacción medicamentosa. Caso clínico

“…Este estímulo se vio potenciado al introducir isoniacida, por su efecto inhibidor de la monoaminooxidasa (IMAO) débil, que resultaba en una menor degradación de la serotonina. 9 Los síntomas no se manifestaron hasta la suspensión del clonazepam, que contrarrestaba la aparición de TS, que comprendía una tríada que incluía alteraciones neuromusculares, hiperactividad autonómica y alteraciones en el estatus mental.…”