Dexamethasone reduces methotrexate biliary elimination and potentiates its hepatotoxicity in rats

Fuksa, Leos; Brčáková, Eva; Kolouchova, Gabriela; Hirsova, Petra; Hroch, Miloš; Cermanova, Jolana; Štaud, František; Mičuda, Stanislav

doi:10.1016/j.tox.2009.11.010

Cited by 25 publications

(11 citation statements)

References 37 publications

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“…Therefore, in our model, we studied the effects of nine combined drugs on methotrexate PK and found that dexamethasone treatment combinations had a significant impact on methotrexate CL, represented by a positive correlation. Animal studies have confirmed that combination with dexamethasone can increase the liver metabolism of methotrexate (Fuksa et al, ), and it is speculated that the reason for the improved methotrexate clearance rate when combined with dexamethasone is due to increased liver metabolism, but further research is needed to confirm the hypothesis.…”

Section: Discussionmentioning

confidence: 98%

Population pharmacokinetics of high‐dose methotrexate in Chinese pediatric patients with medulloblastoma

Shi

Liu

et al. 2020

Biopharm & Drug Disp

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Methotrexate (MTX) pharmacokinetics has substantial inter-individual variability and toxicity. In children with medulloblastoma treated with high-dose methotrexate (HD-MTX), the pharmacokinetic properties of methotrexate have not been established. A total of 660 serum samples from 105 pediatric patients with medulloblastoma were included in a population pharmacokinetic (PPK) analysis of methotrexate by using the nonlinear mixed-effects modeling method. The basic onecompartment population pharmacokinetic model was established by NONMEM software and the first-order conditional estimation (FOCE) method, and the final covariate model was obtained by the stepwise regression method. Weight (WT), creatinine clearance (CrCL), and whether the treatment was combined with dexamethasone (DEX) were covariates that had significant effects on the clearance rate (CL) of the model. The pharmacokinetic equation of CL in the final covariate model was as follows: CL i = 9.23× (1 + 0.0005× (θ CrCL -105.78)) × (1 + 0.0017× (θ WT -16)) × e ηcl,i (L/h), IF (θ DEX ) CL i = 1.19× CL i (L/h). The estimation accuracy of all pharmacokinetic parameters were acceptable (relative standard error < 14.74%). The goodness-of-fit diagram and bootstrap tests indicated that the final PPK model was stable with acceptable predictive ability. The PPK model may be useful for determining personalized medication levels in pediatric medulloblastoma patients undergoing HD-MTX therapy. K E Y W O R D S medulloblastoma, methotrexate, pediatric patients, personalized medicine, population pharmacokinetics

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Section: Discussionmentioning

confidence: 98%

Population pharmacokinetics of high‐dose methotrexate in Chinese pediatric patients with medulloblastoma

Shi

Liu

et al. 2020

Biopharm & Drug Disp

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“…The differences involve both the substrate specificities of particular transporters and the relative fraction of clearance depending on each of them. For example, MTX CL depends mainly on biliary elimination, through Mrp2, in laboratory animals, but is primarily renal in humans with the contribution of MRP2 being unknown .Work in vitro suggests that MRP2 is also a target central to drug interactions , although confirmatory studies in vivo in man are still lacking for some of these interactions. Similarly, the consequences of ABCC2 /MRP2 polymorphisms for MTX CL remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance

Bretagne

Zahr

Gouge

et al. 2014

Brit J Clinical Pharma

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Aims The urinary coproporphyrin I/(I + III) ratio may be a surrogate for MRP2 activity. We conducted a prospective study in patients receiving methotrexate (MTX) to examine the relationship between this ratio and the pharmacokinetics of a MRP2 substrate. Methods Three urine samples were collected from 81 patients for UCP I/(I + III) ratio determination: one before (P1), one at the end of MTX infusion (P2), and one on the day of hospital discharge (P3). Three polymorphisms of ABCC2 were analysed and their relationships with basal UCP I/(I + III) ratio values assessed. All associated drugs were recorded and a drug interaction score (DIS) was assigned. Population pharmacokinetic analysis was conducted to assess whether MTX clearance (MTXCL) was associated with the basal UCP I/(I + III) ratio, its variation during MTX infusion, the DIS or other common covariates. Results The basal UCP I/(I + III) ratio was not associated with ABCC2 polymorphisms and did not differ according to the DIS. Significant changes in the ratio were observed over time, with an increase between P1 and P2 and a decrease at P3 (P < 0.001). No association was found between basal UCP I/(I + III) ratio and MTXCL. The final model indicates that MTXCL was dependent on the change in the ratio between P1 and P3, DIS and creatinine clearance. Conclusion The basal UCP I/(I + III) ratio is not predictive of MTXCL. However, it is sensitive to the presence of MTX, so it is plausible that it reflects a function modified in response to the drug.

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“…Increased hepatotoxicity of methotrexate has been reported during dexamethasone therapy in humans [22] and rats [23]. This may be due to an increase of drug concentration in liver arising from reduced biliary elimination of the drug in the presence of dexamethasone [24]. However, it is not yet known whether or not the pharmacokinetics of vinblastine, cisplatin and adriamycin are affected by co-administration with dexamethasone in human and animals.…”

Section: Discussionmentioning

confidence: 99%

Co-administration of dexamethasone increases severity and accelerates onset day of neutropenia in bladder cancer patients on methotrexate, vinblastine, adriamycin and cisplatin chemotherapy: a retrospective cohort study

Itai

Suga

Hara

et al. 2017

J Pharm Health Care Sci

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BackgroundBladder cancer patients receiving methotrexate, vinblastine, adriamycin and cisplatin (MVAC) chemotherapy are co-administered with dexamethasone as an anti-emetic. We examined whether or not dexamethasone affects the severity and onset day of MVAC-induced severe neutropenia.MethodsThis was a retrospective study of bladder cancer patients treated with MVAC chemotherapy with or without dexamethasone as an antiemetic at Kanazawa University Hospital during January 2005 - December 2009. Patients were categorized into three groups; no dexamethasone use (Dex (−)), dexamethasone on day 2 (Dex 1 day), and dexamethasone on days 2, 3 and 4 (Dex multiday). We evaluated the incidence of grade 3/4 neutropenia and the day of onset of first severe neutropenic episode during the first course of MVAC chemotherapy. Logistic regression was used to investigate whether co-administration of dexamethasone was a risk factor for severe neutropenia.ResultsEpisodes of grade 3/4 neutropenia occurred in 3 out of 6 (50.0%), 11 out of 12 (91.7%) and 6 out of 6 (100%) patients in the Dex (−), Dex 1 day, and Dex multiday groups, respectively. The appearance day of first severe neutropenia in the Dex multiday group (13.2 ± 1.0) was significantly accelerated compared to the Dex (−) group (17.7 ± 2.1). Univariate logistic regression analysis revealed that dexamethasone is a risk factor for severe neutropenia (OR 17.0; 95%CI: 1.3–223.1).ConclusionsCo-administration of dexamethasone for anti-emesis brings forward the first appearance of neutropenia, and increases the severity of neutropenia, in bladder cancer patients receiving MVAC chemotherapy.

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Dexamethasone reduces methotrexate biliary elimination and potentiates its hepatotoxicity in rats

Cited by 25 publications

References 37 publications

Population pharmacokinetics of high‐dose methotrexate in Chinese pediatric patients with medulloblastoma

Population pharmacokinetics of high‐dose methotrexate in Chinese pediatric patients with medulloblastoma

Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance

Co-administration of dexamethasone increases severity and accelerates onset day of neutropenia in bladder cancer patients on methotrexate, vinblastine, adriamycin and cisplatin chemotherapy: a retrospective cohort study

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