Metabolic enzyme induction

Vigilance for drug-drug interactions is required because of the greater number of medications prescribed to elderly patients and enhanced sensitivity to adverse effects. Pharmacokinetic interactions include metabolic enzyme induction or inhibition and protein binding displacement interactions (e.g., divalproex and warfarin). Pharmacodynamic interactions include additive sedation and cognitive toxicity, which increases risk of falls and other impairments. 

Mankowski, D.C. and Ekins, S. (2003) Prediction of human drug metabolizing enzyme induction. Curr. Drug Metab.,... 

Acceleration of hepatic coumarin metabolism enzyme induction, e.g., by carbamazepine, rifampicin ... 

Antimicrobials. Aztreonam, cefamandole, chloramphenicol, ciprofloxacin, co-trimoxazole, erythromycin, fluconazole, itraconazole, ketoconazole, metronidazole, miconazole, ofloxacin and sulphonamides (including co-trimoxazole) increase anticoagulant effect by mechanisms that include interference with warfarin or vitamin K metabolism. Rifampicin and griseofulvin accelerate warfarin metabolism (enzyme induction) and reduce its effect. Intensive broad-spectrum antimicrobials, e.g. eradication regimens for Helicobacter pylori (see p. 630), may increase sensitivity to warfarin by reducing the intestinal flora that produce vitamin K. 

Anticonvulsants. Carbamazepine, phenobarbital and primidone accelerate warfarin metabolism (enzyme induction) the effect of phenytoin is variable. Clonazepam and sodium valproate are safe. 

Hewitt NJ, Lechon MJ, Houston JB, et al. Primary hepatocytes Current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab Rev. 2007 39(1) 159-234. 

Phase I metabolism Phase II metabolism Enzyme induction Enzyme inhibition OS enhancement Receptor interaction Endocrine disruption Immunosuppression Immunostimulation... 

Inoue S. Simultaneous high-performance liquid chromatographic determination of 6 beta-hydroxycortisol and cortisol in urine with fluorescence detection and its application for estimating hepatic drug-metabolizing enzyme induction. J Chromatogr B Biomed Appl 1994 661 15-23. 

Metabolic enzyme induction is operative if no steady state is obtained after five half times and the plasma concentrations decrease. This indicates that the ti/2 is being reduced with repeated dosage, and this is indicative of meta- 0 1,000 2,000 3,000 4,000 5,000... 

Hewitt, N. J., Lechon, M. J. G., Houston, J. B., Hallifax, D., Brown, H. S., Maurel, P., Kenna, J. G., Gustavsson, L., Lohmann, C., Skonberg, C., et al. (2007) Primary hepatocytes current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies. Drug Metab. Rev. 39 (1), 159-234. 

---