Effect of imatinib mesilate on the disposition kinetics of ciclosporin in rats

Kajita, Takashi; Higashi, Yasuhiko; Imamura, Masanobu; Maida, Chieko; Fujii, Youichi; Yamamoto, Ikuyoshi; Miyamoto, Etsuko

doi:10.1211/jpp.58.7.0016

Cited by 13 publications

(8 citation statements)

References 12 publications

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“…35 Concomitant administration of imatinib with inhibitors of both CYP3A4 and Pgp increase not only plasma but also intracellular imatinib concentrations. Dual CYP3A4 and Pgp inhibitors such as verapamil, 9 erythromycin, 36 clarithromycin, 36 ciclosporin, 37,38 ketoconazole, 30 fluconazole, 9,18 and itraconazole 9,18 increase intracellular concentrations of imatinib by inhibiting both its metabolism and its efflux by Pgp and might therefore increase its cellular toxicity.…”

Section: Rosiglitazonementioning

confidence: 99%

“…Imatinib enhances the intestinal absorption of ciclosporin, a CYP3A4 and Pgp substrate, and may increase the pharmacologic effects and possibly toxicity of ciclosporin. 37,38 Moreover, the clearance of simvastatin (a CYP3A4 substrate) was reduced by 70% when associated with imatinib. 13 Administration of imatinib together with metoprolol, a CYP2D6 substrate, resulted in an increase in metoprolol exposure by 23%.…”

Section: Rosiglitazonementioning

confidence: 99%

“…In vitro studies suggest that nilotinib also induces CYP2B6 enzymes. 19 Note that UGT1A1 inhibition has been associated with an increase in bilirubin levels (especially in 1 ciclosporin exposure 37,38 • Inhibition of Pgp and CYP 3A4 by ciclosporin:…”

Section: Drug Interactions With Tyrosine Kinase Inhibitors E81mentioning

confidence: 99%

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Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

Haouala¹,

Widmer²,

Duchosal³

et al. 2011

Blood

215

147

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Several cancer treatments are shifting from traditional, time-limited, nonspecific cytotoxic chemotherapy cycles to continuous oral treatment with specific proteintargeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore, they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacologic mechanisms of interactions between imatinib, dasatinib, and nilotinib and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib mesylate, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory and so is the prospective reporting of unexpected clinical observations. (Blood. 2011;117(8):e75-e87)

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Section: Rosiglitazonementioning

confidence: 99%

Section: Rosiglitazonementioning

confidence: 99%

See 1 more Smart Citation

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

Haouala¹,

Widmer²,

Duchosal³

et al. 2011

Blood

215

147

View full text Add to dashboard Cite

show abstract

“…Both CsA and imatinib are substrates as well as inhibitors of CYP3A4 and P-glycoprotein (P-gp) [1, 3]. Therefore, inhibition of CYP3A4 and/or P-gp by imatinib may increase CsA exposure and vice versa [6, 7]. In view of the narrow therapeutic index of CsA, and as many patients following HSCT already suffer from some degree of renal insufficiency, it is important to avoid supra-therapeutic CsA exposure.…”

Section: Introductionmentioning

confidence: 99%

A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

Atiq

Broers

Andrews

et al. 2016

Eur J Clin Pharmacol

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PurposeCyclosporine A (CsA) and imatinib are both CYP3A4 and P-glycoprotein substrates. Concomitant use after hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (ALL) may therefore result in a pharmacokinetic interaction. Although case reports and a recent small study in children indeed suggested there is a relevant pharmacokinetic interaction, a larger study in adults is lacking. In this study, we assessed the presence and extent of this interaction in patients with CML or Ph+ ALL undergoing HSCT.MethodsFrom a large database containing data of all patients receiving HSCT in our center between 2005 and 2015, we selected 16 patients using this drug combination. The average dose-corrected CsA concentration was calculated before and after initiation of imatinib.ResultsThe average dose-corrected CsA concentration increased during imatinib use in all patients, on average by 94 % (p < 0.001). Based on measured drug concentrations, the CsA dosage needed to be reduced, on average, by 27 % after initiation of imatinib (p = 0.004).ConclusionsImatinib significantly increases CsA concentrations in HSCT patients, putting these patients at increased risk of CsA toxicity. We recommend intensive monitoring of CsA concentrations after initiation of imatinib; a pre-emptive CsA dose reduction of 25 % might be considered.

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“…It has been reported as a narrow therapeutic index drug that may cause severe nephritis and neurotoxicity at high concentration and fails to produce pharmacological effect below minimum effective concentration [13]. CsA is a substrate of CYP3A and P-gp; therefore, it is expected that concomitant administration of cyclosporine with CYP3A/P-gp modulators can alter the pharmacokinetics of cyclosporine and may produce clinically significant interactions [12, 14].…”

Section: Introductionmentioning

confidence: 99%

Effects ofNigella sativaandLepidium sativumon Cyclosporine Pharmacokinetics

Al-Jenoobi

Al‐Suwayeh

Iqbal

et al. 2013

BioMed Research International

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The present study was conducted to investigate the effects of Nigella sativa and Lepidium sativum on the pharmacokinetics of cyclosporine in rabbits. Two groups of animals were treated separately with Nigella sativa (200 mg/kg p.o.) or Lepidium sativum (150 mg/kg p.o.) for eight consecutive days. On the 8th day, cyclosporine (30 mg/kg p.o.) was administered to each group one hour after herbal treatment. Blood samples were withdrawn at different time intervals (0.0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 hrs) from marginal ear vein. Cyclosporine was analyzed using UPLC/MS method. The coadministration of Nigella sativa significantly decreased the C max and AUC0−∞ of cyclosporine; the change was observed by 35.5% and 55.9%, respectively (P ≤ 0.05). Lepidium sativum did not produce any significant change in C max of cyclosporine, although its absorption was significantly delayed compared with control group. A remarkable change was observed in T max and AUC0−t of Lepidium sativum treated group. Our findings suggest that concurrent consumption of Nigella sativa and Lepidium sativum could alter the pharmacokinetics of cyclosporine at various levels.

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Effect of imatinib mesilate on the disposition kinetics of ciclosporin in rats

Cited by 13 publications

References 12 publications

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

A clinically relevant pharmacokinetic interaction between cyclosporine and imatinib

Effects ofNigella sativaandLepidium sativumon Cyclosporine Pharmacokinetics

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