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1.
Biomed Pharmacother ; 164: 114956, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37267638

RESUMO

Mammalian carboxylesterase 1 enzymes can hydrolyze many xenobiotic chemicals and endogenous lipids. We here identified and characterized a mouse strain (FVB/NKI) in which three of the eight Ces1 genes were spontaneously deleted, removing Ces1c and Ces1e partly, and Ces1d entirely. We studied the impact of this Ces1c/d/e deficiency on drug and lipid metabolism and homeostasis. Ces1c/d/e-/- mice showed strongly impaired conversion of the anticancer prodrug irinotecan to its active metabolite SN-38 in plasma, spleen and lung. Plasma hydrolysis of the oral anticancer prodrug capecitabine to 5-DFCR was also profoundly reduced in Ces1c/d/e-/- mice. Our findings resolved previously unexplained FVB/NKI pharmacokinetic anomalies. On a medium-fat diet, Ces1c/d/e-/- female mice exhibited moderately higher body weight, mild inflammation in gonadal white adipose tissue (gWAT), and increased lipid load in brown adipose tissue (BAT). Ces1c/d/e-/- males showed more pronounced inflammation in gWAT and an increased lipid load in BAT. On a 5-week high-fat diet exposure, Ces1c/d/e deficiency predisposed to developing obesity, enlarged and fatty liver, glucose intolerance and insulin resistance, with severe inflammation in gWAT and increased lipid load in BAT. Hepatic proteomics analysis revealed that the acute phase response, involved in the dynamic cycle of immunometabolism, was activated in these Ces1c/d/e-/- mice. This may contribute to the obesity-related chronic inflammation and adverse metabolic disease in this strain. While Ces1c/d/e deficiency clearly exacerbated metabolic syndrome development, long-term (18-week) high-fat diet exposure overwhelmed many, albeit not all, observed phenotypic differences.


Assuntos
Hidrolases de Éster Carboxílico , Síndrome Metabólica , Pró-Fármacos , Animais , Feminino , Masculino , Camundongos , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Inflamação , Irinotecano , Lipídeos , Mamíferos , Obesidade/metabolismo
2.
Acta Pharm Sin B ; 13(2): 618-631, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36873183

RESUMO

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 -/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 -/- background (TgCES1). Ces1 -/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 -/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 -/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 -/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

3.
Pharmaceuticals (Basel) ; 15(7)2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35890158

RESUMO

The extrapolation of drug exposure between species remains a challenging step in drug development, contributing to the low success rate of drug approval. As a consequence, extrapolation of toxicology from animal models to humans to evaluate safe, first-in-human (FIH) doses requires high safety margins. We hypothesized that a human-CYP3A4-expressing transgenic (Cyp3aXAV) mouse is a more predictive model for human drug exposure of CYP3A4-metabolized small-molecule drugs. Population pharmacokinetic models based on wild-type (WT) and Cyp3aXAV mouse pharmacokinetic data of oral lorlatinib, brigatinib, ribociclib and fisogatinib were allometrically scaled and compared to human exposure. Extrapolation of the Cyp3aXAV mouse model closely predicted the observed human exposure for lorlatinib and brigatinib with a 1.1-fold and 1.0-fold difference, respectively, compared to a 2.1-fold and 1.9-fold deviation for WT-based extrapolations of lorlatinib and brigatinib, respectively. For ribociclib, the extrapolated WT mouse model gave better predictions with a 1.0-fold deviation compared to a 0.3-fold deviation for the extrapolated Cyp3aXAV mouse model. Due to the lack of a human population pharmacokinetic model for fisogatinib, only median maximum concentration ratios were calculated, resulting in ratios of 1.0 and 0.6 for WT and Cyp3aXAV mice extrapolations, respectively. The more accurate predictions of human exposure in preclinical research based on the Cyp3aXAV mouse model can ultimately result in FIH doses associated with improved safety and efficacy and in higher success rates in drug development.

4.
Front Pharmacol ; 13: 855000, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35308219

RESUMO

The psychedelic alkaloid ibogaine is increasingly used as an oral treatment for substance use disorders, despite being unlicensed in most countries and having reported adverse events. Using wild-type and genetically modified mice, we investigated the impact of mouse (m)Abcb1a/1b and Abcg2 drug efflux transporters, human and mouse OATP drug uptake transporters, and the CYP3A drug-metabolizing complex on the pharmacokinetics of ibogaine and its main metabolites. Following oral ibogaine administration (10 mg/kg) to mice, we observed a rapid and extensive conversion of ibogaine to noribogaine (active metabolite) and noribogaine glucuronide. Mouse Abcb1a/1b, in combination with mAbcg2, modestly restricted the systemic exposure (plasma AUC) and peak plasma concentration (Cmax) of ibogaine. Accordingly, we found a ∼2-fold decrease in the relative recovery of ibogaine in the small intestine with fecal content in the absence of both transporters compared to the wild-type situation. Ibogaine presented good intrinsic brain penetration even in wild-type mice (brain-to-plasma ratio of 3.4). However, this was further increased by 1.5-fold in Abcb1a/1b;Abcg2 -/- mice, but not in Abcg2 -/- mice, revealing a stronger effect of mAbcb1a/1b in restricting ibogaine brain penetration. The studied human OATP transporters showed no major impact on ibogaine plasma and tissue disposition, but the mOatp1a/1b proteins modestly affected the plasma exposure of ibogaine metabolites and the tissue disposition of noribogaine glucuronide. No considerable role of mouse Cyp3a knockout or transgenic human CYP3A4 overexpression was observed in the pharmacokinetics of ibogaine and its metabolites. In summary, ABCB1, in combination with ABCG2, limits the oral availability of ibogaine, possibly by mediating its hepatobiliary and/or direct intestinal excretion. Moreover, ABCB1 restricts ibogaine brain penetration. Variation in ABCB1/ABCG2 activity due to genetic variation and/or pharmacologic inhibition might therefore affect ibogaine exposure in patients, but only to a limited extent. The insignificant impact of human CYP3A4 and OATP1B1/1B3 transporters may be clinically advantageous for ibogaine and noribogaine use, as it decreases the risks of undesirable drug interactions or interindividual variation related to CYP3A4 and/or OATP activity.

5.
Pharmacol Res ; 178: 105954, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34700018

RESUMO

Abemaciclib is the third cyclin-dependent kinase (CDK) 4/6 inhibitor approved for the treatment of breast cancer and currently under investigation for other malignancies, including brain cancer. Primarily CYP3A4 metabolizes abemaciclib, forming three active metabolites (M2, M20 and M18) that are likely relevant for abemaciclib efficacy and toxicity. We investigated the impact of ABCB1 (P-gp), ABCG2 (BCRP) and CYP3A on the pharmacokinetics and tissue distribution of abemaciclib and its metabolites using genetically modified mice. In vitro, abemaciclib was efficiently transported by hABCB1 and mAbcg2, and slightly by hABCG2, but the active metabolites were transported even better. Upon oral administration of 10 mg/kg abemaciclib, absence of Abcg2 and especially Abcb1a/1b significantly increased the plasma AUC0-24 h and Cmax of M2 and M18. Furthermore, the relative brain penetration of abemaciclib, M2 and M20 was dramatically increased by 25-, 4- and 60-fold, respectively, in Abcb1a/1b;Abcg2-/- mice, and to a lesser extent in single Abcb1a/1b- or Abcg2-deficient mice. The recovery of all active compounds in the small intestine content was profoundly reduced in Abcb1a/1b;Abcg2-/- mice, with smaller effects in single Abcb1a/1b-/- and Abcg2-/- mice. Our results indicate that Abcb1a/1b and Abcg2 cooperatively and profoundly limit the brain penetration of abemaciclib and its active metabolites, and likely also participate in their hepatobiliary or direct intestinal elimination. Moreover, transgenic human CYP3A4 drastically reduced the abemaciclib plasma AUC0-24 h and Cmax by 7.5- and 5.6-fold, respectively, relative to Cyp3a-/- mice. These insights may help to optimize the clinical development of abemaciclib, especially for the treatment of brain malignancies.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Aminopiridinas , Benzimidazóis , Citocromo P-450 CYP3A , Proteínas de Neoplasias , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminopiridinas/metabolismo , Aminopiridinas/farmacologia , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Encéfalo/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Cães , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Preparações Farmacêuticas/metabolismo
6.
J Pharm Biomed Anal ; 203: 114225, 2021 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-34242947

RESUMO

Abemaciclib is the third cyclin-dependent kinase 4 and 6 inhibitor approved for the treatment of advanced or metastatic breast cancer. In humans, abemaciclib is extensively metabolized by CYP3A4 with the formation of three active metabolites: N-desethylabemaciclib (M2), hydroxyabemaciclib (M20) and hydroxy-N-desethylabemaciclib (M18). These metabolites showed similar potency compared to the parent drug and were significantly abundant in plasma circulation. Thus, M2, M20, and M18 may contribute to the clinical activity of abemaciclib. For this reason, an UHPLC-MS/MS method for the simultaneous quantification of abemaciclib and its active metabolites in human and mouse plasma was developed and validated to support further clinical or preclinical investigations on this drug. Samples were processed by protein precipitation with acetonitrile, followed by supernatant dilution and filtration. Chromatographic separation was performed on a Kinetex C18 column (150 × 2.1 mm ID, 2.6 µm) using gradient elution with 10 mM ammonium bicarbonate in water (eluent A) and in methanol-water (9:1, v/v, eluent B). This method was selective, linear, accurate and precise within the range of 1-600 ng/mL for abemaciclib, 0.5-300 ng/mL for M2 and M20, and 0.2-120 ng/mL for M18. Furthermore, stability of the analytes in human and mouse plasma samples in several conditions was demonstrated. Finally, this assay was successfully used in a preclinical pharmacokinetic study, where abemaciclib and its active metabolites were identified and quantified. Inter-species differences between human and mouse samples were encountered, especially in the formation of M20, where isomers of this compound were detected in mouse plasma, but not in human plasma. This was confirmed by high resolution-mass spectrometry (HR-MS) measurements.


Assuntos
Preparações Farmacêuticas , Espectrometria de Massas em Tandem , Aminopiridinas , Animais , Benzimidazóis , Cromatografia Líquida de Alta Pressão , Humanos , Camundongos , Reprodutibilidade dos Testes
7.
Eur J Pharm Sci ; 159: 105740, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33524505

RESUMO

The promising anticancer drug milciclib potently inhibits cyclin-dependent kinase (CDK) 2 and tropomyosin receptor kinase (TRK) A, and is currently in phase II clinical studies. To characterize factors affecting milciclib pharmacokinetics, we investigated whether milciclib is a substrate of the multidrug efflux and uptake transporters ABCB1 (P-gp), ABCG2 (BCRP), and OATP1A/1B, and the drug-metabolizing enzyme CYP3A, using genetically-modified mouse models and Madin-Darby Canine Kidney (MDCK-II) cells. In vitro, milciclib was transported by mAbcg2, and this was inhibited by the ABCG2 inhibitor Ko143. Upon oral administration of milciclib, its plasma exposure in Abcb1a/1b-/-, Abcg2-/-, and Abcb1a/1b;Abcg2-/- mice was similar to that found in wild-type mice. Milciclib showed good brain penetration even in wild-type mice (brain-to-plasma ratio of 1.2), but this was further increased by 5.2-fold when both Abcb1 and Abcg2 were ablated, and to a lesser extent in single Abcb1- or Abcg2-deficient mice. Oatp1a/1b deficiency had only a minor impact on the milciclib plasma AUC0-24h and Cmax. The milciclib AUC0-8h increased 1.9-fold in Cyp3a-/- mice but decreased only 1.3-fold upon overexpression of human CYP3A4. Thus, ABCB1 and ABCG2 cooperatively limit milciclib brain penetration. The low impact of OATP1 and CYP3A could be clinically favorable for milciclib, reducing the risks of unintended drug-drug interactions or interindividual variation in CYP3A4 activity.


Assuntos
Citocromo P-450 CYP3A , Preparações Farmacêuticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Cães , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Distribuição Tecidual
8.
Clin Pharmacokinet ; 59(12): 1501-1520, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33029704

RESUMO

Palbociclib, ribociclib, and abemaciclib are inhibitors of the cyclin-dependent kinases 4 and 6 approved for the treatment of locally advanced or metastatic breast cancer. In this review, we provide an overview of the available clinical pharmacokinetic and pharmacodynamic characteristics of these novel drugs, summarize the results of food-effect and drug-drug interaction studies, and highlight exposure-response and exposure-toxicity relationships. All three drugs exhibit a large inter-individual variability in exposure (coefficient of variation range 40-95% for minimum plasma concentration), are extensively metabolized by cytochrome P450 3A4, and have their brain penetration limited by efflux transporters. Abemaciclib has three active metabolites with similar potency that are clinically relevant (i.e., M2, M20, M18), whereas the metabolites of palbociclib and ribociclib are not of clinical significance. Pharmacokinetic exposure increases in a dose-proportional manner for palbociclib, whereas exposure increases under- and over-proportionally with an increasing dose for abemaciclib and ribociclib, respectively. High exposure is associated with an increased risk of neutropenia, and for ribociclib also to corrected QT prolongation. For abemaciclib, a clear exposure-efficacy relationship has been described, while for palbociclib and ribociclib exposure-response analyses remain inconclusive. Future studies are needed to address exposure-efficacy relationships to further improve dosing.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias da Mama , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases/farmacocinética , Aminopiridinas/farmacocinética , Benzimidazóis/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Piperazinas/farmacocinética , Purinas/farmacocinética , Piridinas/farmacocinética
9.
J Pharm Biomed Anal ; 190: 113516, 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-32784092

RESUMO

Milciclib is a promising cyclin-dependent kinase inhibitor currently in phase II clinical trials to treat several types of cancer. The first bioanalytical method for the quantitative analysis of milciclib in several biomatrices using liquid chromatography-tandem mass spectrometry is described here. This method was fully validated in human plasma according to FDA and EMA guidelines, and partially validated in mouse plasma, homogenates of mouse brain, kidney, liver, small intestine, spleen, and tissue culture medium. Palbociclib, an analog compound, was used as internal standard. A simple and fast sample pre-treatment by protein precipitation with acetonitrile was used, leading to efficient extraction of the analyte with recoveries between 95-100%. Chromatographic separation was achieved with a C18 analytical column and a gradient elution using 10 mM ammonium bicarbonate in water and 10 mM ammonium bicarbonate in water-methanol (1:9, v/v). This assay was selective, accurate, precise and linear in the concentration range of 1-1000 ng/mL. Moreover, samples above the upper limit of quantification can be integrally diluted up to 10-fold prior to analysis. The use of human plasma as a surrogate matrix to quantify milciclib in tissue culture medium and mouse matrices resulted in acceptable accuracy and precision, however tissue culture medium samples required a dilution with human plasma prior the pre-treatment. All performance parameters of the method complied with the acceptance criteria recommended by the guidelines, except for the carry-over, which was slightly above (22.9% of the lower limit of quantification) the recommended percentage (20%). Therefore, additional measures were taken to assure data integrity. Stability of milciclib in all matrices was evaluated, and in some matrices the analyte was unstable under the tested conditions. It is therefore recommended to keep these samples as briefly as possible at room temperature during the pre-treatment, and to store them at -70 °C to avoid analyte degradation. This method was successfully applied to support preclinical pharmacokinetic studies of milciclib.


Assuntos
Plasma , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida , Meios de Cultura , Humanos , Camundongos , Inibidores de Proteínas Quinases , Reprodutibilidade dos Testes
10.
Artigo em Inglês | MEDLINE | ID: mdl-32464539

RESUMO

A simple and rapid bioanalytical method was developed for the simultaneous quantification of irinotecan and SN-38 in mouse plasma and tissue homogenates using High-Performance Liquid Chromatography with Fluorescence detection (HPLC-FL). Camptothecin was used as internal standard and protein precipitation with acetonitrile-methanol (1:1, v/v) followed by acidification with 0.5 M hydrochloric acid was used for sample pre-treatment. The analytes and the internal standard were detected using an excitation and emission wavelength of 368 and 515 nm, respectively. The linearity, selectivity, accuracy and precision, carry-over, limit of detection and lower limit of quantification of the method are described. The method was linear from 7.5 to 1500 ng/mL for irinotecan and from 5 to 1000 ng/mL for SN-38. For all matrices, the accuracy bias and precision variation were within ±15% and ≤15%, respectively. This method was successfully applied to study the pharmacokinetics of irinotecan and SN-38 using in vivo mouse models.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Irinotecano/sangue , Espectrometria de Fluorescência/métodos , Animais , Camptotecina , Irinotecano/análise , Irinotecano/química , Irinotecano/farmacocinética , Limite de Detecção , Modelos Lineares , Camundongos , Reprodutibilidade dos Testes , Distribuição Tecidual
11.
Mol Pharm ; 16(9): 3842-3852, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31329454

RESUMO

Ribociclib is a CDK4/6 inhibitor recently approved for the treatment of some types of breast cancer in combination with an aromatase inhibitor. It is currently investigated in the clinic to treat other malignancies, including brain tumors. Using in vitro and genetically modified mouse models, we investigated the effect of the multidrug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing CYP3A enzymes on ribociclib pharmacokinetics and tissue distribution. In vitro, ribociclib was avidly transported by human ABCB1, but not by human ABCG2 and only modestly by mouse Abcg2. Upon oral administration at 20 mg/kg, the plasma AUC0-24h of ribociclib was increased by 2.3-fold, and its terminal elimination was delayed in Abcb1a/1b-/-;Abcg2-/- compared to wild-type mice. The brain-to-plasma ratios of ribociclib were increased by at least 23-fold relative to wild-type mice in Abcb1a/1b-/-;Abcg2-/- and Abc1a/1b-/- mice, but not noticeably in Abcg2-/- mice. Oral coadministration of elacridar, an ABCB1 and ABCG2 inhibitor, increased the brain penetration of ribociclib in wild-type mice to the same level as seen in Abcb1a/1b-/-;Abcg2-/- mice. Plasma exposure of ribociclib further decreased by 3.8-fold when transgenic human CYP3A4 was overexpressed in Cyp3a-deficient mice. Ribociclib penetration into the brain is thus drastically limited by ABCB1 in the blood-brain barrier, but coadministration of elacridar can fully reverse this process. Moreover, human CYP3A4 can extensively metabolize ribociclib and strongly restrict its oral bioavailability. The insights obtained from this study may be useful to further optimize the clinical application of ribociclib, especially for the treatment of (metastatic) brain tumors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Aminopiridinas/administração & dosagem , Aminopiridinas/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Purinas/administração & dosagem , Purinas/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Acridinas/farmacologia , Administração Oral , Aminopiridinas/metabolismo , Animais , Disponibilidade Biológica , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Cães , Feminino , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Purinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Distribuição Tecidual , Transdução Genética
12.
Anal Bioanal Chem ; 411(20): 5331-5345, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31209549

RESUMO

A novel method was developed and validated for the quantification of the three approved CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) in both human and mouse plasma and mouse tissue homogenates (liver, kidney, spleen, brain, and small intestine) using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). For all matrices, pretreatment was performed using 50 µL of sample by protein precipitation with acetonitrile, followed by dilution of the supernatant. Chromatographic separation of the analytes was done on a C18 column using gradient elution. A full validation was performed for human plasma, while a partial validation was executed for mouse plasma and mouse tissue homogenates. The method was linear in the calibration range from 2 to 200 ng/mL, with a correlation coefficient (r) ≥0.996 for each analyte. For both human and mouse plasma, the accuracy and precision were within ±15% and ≤15%, respectively, for all concentrations, except for the lower limit of quantification, where they were within ±20% and ≤20%, respectively. A fit-for-purpose strategy was followed for tissue homogenates, and the accuracy and precision were within ±20% and ≤20%, respectively, for all concentrations. Stability of all analytes in all matrices at different processing and storage conditions was tested; ribociclib and palbociclib were unstable in most tissue homogenates and conditions were modified to increase the stability. The method was successfully applied for the analysis of mouse samples from preclinical studies. A new ribociclib metabolite was detected in mouse plasma samples with the same m/z transition as the parent drug.


Assuntos
Aminopiridinas/análise , Benzimidazóis/análise , Cromatografia Líquida/métodos , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Piperazinas/análise , Inibidores de Proteínas Quinases/análise , Purinas/análise , Piridinas/análise , Espectrometria de Massas em Tandem/métodos , Aminopiridinas/farmacologia , Animais , Benzimidazóis/farmacologia , Humanos , Camundongos , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Piridinas/farmacologia
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