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imatinib CYP2C8

Janne T Backman, Anne M Filppula, Mikko Niemi, Pertti J Neuvonen
During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i...
January 2016: Pharmacological Reviews
Muhammad Suleman Khan, Daniel T Barratt, Andrew A Somogyi
1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively)...
2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
A M Filppula, A Tornio, M Niemi, P J Neuvonen, J T Backman
Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-∞) of N-desmethylimatinib by 56 and 48% (P < 0...
September 2013: Clinical Pharmacology and Therapeutics
Anne M Filppula, Mikko Neuvonen, Jouko Laitila, Pertti J Neuvonen, Janne T Backman
Recent data suggest that the role of CYP3A4 in imatinib metabolism is smaller than presumed. This study aimed to evaluate the quantitative importance of different cytochrome P450 (P450) enzymes in imatinib pharmacokinetics. First, the metabolism of imatinib was investigated using recombinant P450 enzymes and human liver microsomes with P450 isoform-selective inhibitors. Thereafter, an in silico model for imatinib was constructed to perform pharmacokinetic simulations to assess the roles of P450 enzymes in imatinib elimination at clinically used imatinib doses...
January 2013: Drug Metabolism and Disposition: the Biological Fate of Chemicals
A M Filppula, J Laitila, P J Neuvonen, J T Backman
BACKGROUND AND PURPOSE: Imatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Because competitive inhibition of CYP3A4/5 does not explain these in vivo interactions, we investigated the reversible and time-dependent inhibitory effects of imatinib and its main metabolite N-desmethylimatinib on CYP2C8 and CYP3A4/5 in vitro. EXPERIMENTAL APPROACH: Amodiaquine N-deethylation and midazolam 1'-hydroxylation were used as marker reactions for CYP2C8 and CYP3A4/5 activity...
April 2012: British Journal of Pharmacology
Noelia Nebot, Severine Crettol, Fabrizio d'Esposito, Bruce Tattam, David E Hibbs, Michael Murray
BACKGROUND AND PURPOSE: Imatinib is a clinically important inhibitor of tyrosine kinases that are dysregulated in chronic myelogenous leukaemia and gastrointestinal stromal tumours. Inter-individual variation in imatinib pharmacokinetics is extensive, and influences drug safety and efficacy. Hepatic cytochrome P450 (CYP) 3A4 has been implicated in imatinib N-demethylation, but the clearance of imatinib decreases during prolonged therapy. CYP3A phenotype correlates with imatinib clearance at the commencement of therapy, but not at steady state...
November 2010: British Journal of Pharmacology
David L Deremer, Celalettin Ustun, Kavita Natarajan
BACKGROUND: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI) formerly known as AMN107, was approved by the US Food and Drug Administration (FDA) on October 29, 2007, for the treatment of adult patients with chronic-phase (CP) and accelerated-phase (AP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) resistant to or intolerant of prior treatment that included imatinib. OBJECTIVE: The purpose of this review was to evaluate the pharmacology, pharmacokinetic properties, and pharmacodynamic properties of nilotinib; results of clinical trials in patients with CML, Ph+ acute lymphoblastic leukemia (ALL), and gastrointestinal stromal tumors (GISTs); and potential drug interactions...
November 2008: Clinical Therapeutics
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