The effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite: paracetamol glucuronide

Karbownik, Agnieszka; Szałek, Edyta; Sobańska, Katarzyna; Połom, Wojciech; Grabowski, Tomasz; Biczysko-Murawa, Anna; Matuszewski, Marcin; Wolc, Anna; Grześkowiak, Edmund

doi:10.1007/s13318-014-0191-z

Cited by 5 publications

(4 citation statements)

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“…The study on the sunitinib and paracetamol interaction in rabbits proved that concomitant administration of the drugs (25 mg p.o ., 35 mg/kg b.w. i.v., respectively), contributed to lower exposure and faster clearance of paracetamol [ 21 ]. Furthermore, the same authors observed that another TKI – erlotinib, modified the metabolism of paracetamol, reducing its glucuronidation and intensifying its sulphation.…”

Section: Discussionmentioning

confidence: 99%

The concomitant use of lapatinib and paracetamol - the risk of interaction

et al. 2018

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SummaryLapatinib is a tyrosine kinase inhibitor used for the treatment of breast cancer. Paracetamol is an analgesic commonly applied to patients with mild or moderate pain and fever. Cancer patients are polymedicated, which involves high risk of drug interactions during therapy. The aim of the study was to assess the interaction between lapatinib and paracetamol in rats. The rats were divided into three groups of eight animals in each. One group received lapatinib + paracetamol (IL + PA), another group received lapatinib (IIL), whereas the last group received paracetamol (IIIPA). A single dose of lapatinib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. Plasma concentrations of lapatinib, paracetamol and its metabolites – glucuronide and sulphate, were measured with the validated HPLC-MS/MS method and HPLC-UV method, respectively. The pharmacokinetic parameters of both drugs were calculated using non-compartmental methods. The co-administration of lapatinib and paracetamol increased the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) of lapatinib by 239.6% (p = 0.0030) and 184% (p = 0.0011), respectively. Lapatinib decreased the paracetamol AUC0-∞ by 48.8% and Cmax by 55.7%. In the IL + PA group the Cmax of paracetamol glucuronide was reduced, whereas the Cmax of paracetamol sulphate was higher than in the IIIPA group. Paracetamol significantly affected the enhanced plasma exposure of lapatinib. Additionally, lapatinib reduced the concentrations of paracetamol. The co-administration of lapatinib decreased the paracetamol glucuronidation but increased the sulphation. The findings of this study may be of clinical relevance to patients requiring analgesic therapy.

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Section: Discussionmentioning

confidence: 99%

The concomitant use of lapatinib and paracetamol - the risk of interaction

et al. 2018

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“…In the I S+PA group we also observed increased C max and AUC 0-∞ of paracetamol sulphate by 2.1-and 2.7-fold, respectively with a simultaneous increase in paracetamol sulphate/paracetamol ratio for C max and AUC 0-∞ (p = 0.0003 and p = 0.0003, respectively). Karbownik et al [36][37][38] conducted an in vivo study and proved that other TKIs, i.e. erlotinib, lapatinib and sunitinib significantly affected the PK of paracetamol.…”

Section: The Influence Of Sorafenib On the Pharmacokinetics Of Paracementioning

confidence: 99%

In vivo assessment of the drug interaction between sorafenib and paracetamol in rats

Karbownik

Sobańska

Grabowski

et al. 2020

Cancer Chemother Pharmacol

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Purpose Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI) used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. Neoplastic diseases are the cause of pain, which may occur regardless of the stage of the disease. Paracetamol is a non-opioid analgesic used alone or in combination with opioids for the treatment of cancer pain. Numerous studies have pointed out changes in the pharmacokinetic parameters of TKIs when co-administered with paracetamol. The aim of the study was to assess drug-drug interactions (DDIs) between sorafenib and paracetamol. Methods Rats were divided into three groups, each consisting of eight animals. The first group received sorafenib (II S), the second group received sorafenib + paracetamol (I S+PA), whereas the third group received only paracetamol (III PA). A single dose of sorafenib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. The plasma concentrations of sorafenib and its metabolite-N-oxide as well as paracetamol and its glucuronide and sulphate metabolites were measured using validated high-performance liquid chromatography (HPLC) method with ultraviolet detection. Results The co-administration of sorafenib and paracetamol increased the maximum concentration (C max) of paracetamol by 33% (p = 0.0372). In the I S+ PA group the C max of paracetamol glucuronide was reduced by 48% (p = < 0.0001), whereas the C max of paracetamol sulphate was higher by 153% (p = 0.0012) than in the III PA group. Paracetamol increased sorafenib and sorafenib N-oxide C max by 60% (p = 0.0068) and 83% (p = 0.0023), respectively. Conclusions A greater knowledge of DDI between sorafenib and paracetamol may help adjust dose properly and avoid toxicity effects in individual patients.

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“… The green dots are the data adopted from the work of [ 61 ]. CYP protein mediated hepatic clearance was parameterised with Vmax = 40 μmol/L/min, Km = 10 μmol/L and considering a liver concentration of the enzyme of 1μmol/L.…”

Section: Supporting Informationmentioning

confidence: 99%

Development and validation of a physiology-based model for the prediction of pharmacokinetics/toxicokinetics in rabbits

et al. 2018

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The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations.

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The effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite: paracetamol glucuronide

Cited by 5 publications

References 39 publications

The concomitant use of lapatinib and paracetamol - the risk of interaction

The concomitant use of lapatinib and paracetamol - the risk of interaction

In vivo assessment of the drug interaction between sorafenib and paracetamol in rats

Development and validation of a physiology-based model for the prediction of pharmacokinetics/toxicokinetics in rabbits

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