High Extraction Ratio Research Articles

An ultra-fast green ultra-high-performance liquid chromatography-tandem mass spectrometry method for estimating the in vitro metabolic stability of zotizalkib in human liver microsomes.

Zotizalkib (ZTK, TPX-0131) is a fourth-generation highly effective inhibitor of wild-type anaplastic lymphoma kinase (ALK) and ALK-resistant mutations that can penetrate the central nervous system. It exhibited greater potency compared to all five officially approved ALK inhibitors. The aim of this study was to develop a rapid, accurate, eco-friendly, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for measuring the concentration of ZTK in human liver microsomes (HLMs). The validation aspects of the current UHPLC-MS/MS methodology in the HLMs were conducted in accordance with the bioanalytical method validation standards specified by the US Food and Drug Administration. ZTK and encorafenib were separated using an Agilent C8 column (Eclipse Plus) and an isocratic mobile phase. The calibration curve for the developed ZTK exhibited a linear relationship within the concentration range of 1-3000ng/mL. The results from the Analytical Green-ness Metric Approach program (0.76) suggested that the created method demonstrated a significant degree of environmental sustainability. The in vitro half-life (t1/2) and intrinsic clearance (Clint) of ZTK were determined to be 15.79min and 51.35mL/min/kg, respectively that suggests the ZTK exhibits characteristics similar to those of a medication with a high extraction ratio. These approaches are crucial for the progress of novel pharmaceutical development, especially in improving metabolic stability.

An ultra-fast ultra-high-performance liquid chromatography-tandem mass spectrometry method for estimating the in vitro metabolic stability of palbociclib in human liver microsomes: In silico study for metabolic lability, absorption, distribution, metabolism, and excretion features, and DEREK alerts screening.

Palbociclib (Ibrance; Pfizer) was approved for the management of metastatic breast cancer characterized by hormone receptor-positive/human epidermal growth factor receptor 2 negative status. The objective of this study was to create a fast, precise, environmentally friendly, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry approach for quantifying palbociclib (PAB) in human liver microsomes with the application for assessing metabolic stability. The validation features were performed in agreement with the bioanalytical method validation standards outlined by the US Food and Drug Administration. The StarDrop software (WhichP450 and DEREK modules) was used in screening the metabolic lability and structural alerts of PAB. The separation of PAB and encorafenib (as an internal standard) was achieved on a C8 column, employing an isocratic mobile phase. The inter-day and intra-day accuracy and precision ranged from -6.00% to 4.64% and from -2.33% to 3.13%, respectively. The constructed calibration curve displayed a linearity in the range of 1-3000ng/mL. The sensitivity of the established approach was proven by the lower limit of quantification of 0.73ng/mL. The Analytical GREEness calculator results revealed the high level of greenness of the developed method. The PAB's metabolic stability (t1/2 of 18.5 min and a moderate clearance (Clint) of 44.8mL/min/kg) suggests a high extraction ratio medication that matched the WhichP450 software results.

Ultra-fast UPLC–MS/MS approach for estimating X-376 in human liver microsomes: Evaluation of metabolic stability via in silico software and in vitro analysis

X-376 is a novel anaplastic lymphoma kinase (ALK) inhibitor that is capable of penetrating the blood brain barrier. This makes it suitable for use in patients with ALK-positive non-small cell lung cancer (NSCLC) who have metastases in the central nervous system. This study developed a highly sensitive, fast, eco-friendly, and reliable UPLC-MS/MS approach to quantify X-376 in human liver microsomes (HLMs). This approach was used to evaluate X-376's metabolic stability in HLMs in vitro. The UPLC-MS/MS analytical technique validation followed US-FDA bio-analytical method validation guidelines. StarDrop software, containing P450 metabolic and DEREK modules, was utilized to scan X-376's chemical structure for metabolic lability and hazardous warnings. X-376 and Encorafenib (ENF as internal standard) were resoluted on the Eclipse Plus C18 column utilizing an isocratic mobile phase method. The X-376 calibration curve was linear from 1 to 3000 ng/mL. The precision and accuracy of this study's UPLC-MS/MS approach were tested for intra- and inter-day measurements. Inter-day accuracy was −1.32% to 9.36% while intra-day accuracy was −1.5% to 10.00%. The intrinsic clearance (Clint) and in vitro half-life (t1/2) of X-376 were 59.77 mL/min/kg and 13.56 min. The high extraction ratio of X-376 supports the 50 mg twice-daily dose for ALK-positive NSCLC and CNS metastases patients. In silico software suggests that simple structural changes to the piperazine ring or group substitution in drug design may improve metabolic stability and safety compared to X-376.

Removal of molybdenum by TBP-TRPO extraction in sodium isopolytungstate solution

A new process was proposed for extracting molybdenum from tungsten solutions in acidic tungsten-molybdenum mixed solution. The extraction ratio of molybdenum reached 70 % and the tungsten-molybdenum separation factors reached 400 with the hydrogen peroxide dosage of nH2O2/n(Mo) = 2 (nH2O2/n(W + Mo) = 0.3) for the molybdenum-containing isopolytungstate sodium solution. The experimental conditions resulted in the yield of only 20 % of the traditional method (nH2O2/n(W + Mo) = 1.5–2). The organic phases consisted of 2 % TRPO and 60 % TBP. The saturated extraction capacity of molybdenum was found to be 10 g/L. The solution of 0.3 mol/L sodium bicarbonate was used as the stripping agent. With the temperature of 25 ℃, stripping time of 6 min, and the phase ratio of (O/A)2, the stripping ratio of molybdenum was 90 % and that of tungsten was 70 %. The extraction mechanism of TBP-TRPO and the hydrogen peroxide coordination were analyzed using Raman and infrared analyses. The process has a high industrial potential due to its low hydrogen peroxide dosage, high molybdenum extraction ratio, high separation factor, and low cost.

Fundamental experiment and numerical simulation of pre‐ionized inert gas plasma MHD electrical power generation

AbstractThe experiments of pre‐ionized inert gas plasma MHD electrical power generation are conducted, and the performance and plasma behavior in the experimental generator are examined through time‐dependent r‐_ two‐dimensional numerical simulation. In the experiment, an enthalpy extraction ratio of 4.01% has been obtained with a disk‐shaped MHD generator with radio‐frequency pre‐ionization. In the numerical simulation, at an assumed inlet electron temperature around 5600 K (inlet ionization degree 0:10 × 10−4)_6600 K (1:36 × 10−4), the plasma structure is similar to the non‐uniform structure observed in the experiment. An enthalpy extraction ratio around 2_5% matches well with that in the experiment. At a suitable inlet electron temperature of 7000 K (3:15 × 10−4)_8000 K (1:79 × 10−3), although non‐uniform plasma structure still occurs, a high enthalpy extraction ratio over 10% is expected.

Analysis of the interplay of physiological response to food intake and drug properties in food-drug interactions

The effect of food on oral drug absorption is determined by the complex interplay among gut physiological factors and drug properties. The currently used dissolution testing and classification systems (biopharmaceutics classification system, BCS or biopharmaceutics drug disposition classification system, BDDCS) do not account for dynamic changes in gastrointestinal physiology caused by food intake. This study aimed to identify key drug properties that influence food effect (FE) using supervised machine learning approaches. The analysis showed that drugs with high logP, dose number, and extraction ratio have a higher probability of positive FE, while drugs with low permeability and high efflux saturation index have a greater likelihood of negative FE. Weakly acidic drugs also showed a greater probability of positive FE, particularly at pKa >4.3. The importance of drug properties in predicting FE was ranked as logP, dose number, extraction ratio, pKa, and permeability. The accuracy of FE prediction using the models was compared with BCS and extended clearance classification system (ECCS). Overall, the likelihood or magnitude of FE depends on physiological changes to food intake such as altered bile acid secretion rate, intestinal metabolism, transport kinetics, and gastric emptying time, which should be considered along with drug properties (e.g., solubility, logP, and ionization) in predicting FE of orally administered drugs.

Model-informed drug development: The mechanistic HSK3486 physiologically based pharmacokinetic model informing dose decisions in clinical trials of specific populations.

HSK3486, a central nervous system inhibitor, has demonstrated superior anesthetic properties in comparison with propofol. Owing to the high liver extraction ratio of HSK3486 and the limited susceptibility to the multi-enzyme inducer, rifampicin, the indicated population of HSK3486 is substantial. Nevertheless, in order to expand the population with indications, it is crucial to assess the systemic exposure of HSK3486 in specific populations. Moreover, the main metabolic enzyme of HSK3486 is UGT1A9, which shows a gene polymorphism in the population. Thus, to scientifically design the dose regimen for clinical trials in specific populations, a HSK3486 physiologically based pharmacokinetic model was developed in 2019 to support model-informed drug development (MIDD). Several untested scenarios of HSK3486 administration in specific populations, and the effect of the UGT1A9 gene polymorphism on HSK3486 exposure were estimated as well. The predicted systemic exposure was increased slightly in patients with hepatic impairment and in the elderly, consistent with later clinical trial data. Meanwhile, there was no change in the systemic exposure of patients with severe renal impairment and in neonates. However, under the same dose, the predicted exposure of pediatric patients aged 1month to 17years was decreased significantly (about 21%-39%). Although these predicted results in children have not been validated by clinical data, they are comparable to clinical findings for propofol in children. The dose of HSK3486 in pediatrics may need to be increased and can be adjusted according to the predicted results. Moreover, the predicted HSK3486 systemic exposure in the obese population was increased by 28%, and in poor metabolizers of UGT1A9 might increase by about 16%-31% compared with UGT1A9 extensive metabolizers. Combined with the relatively flat exposure-response relationship for efficacy and safety (unpublished), obesity and genetic polymorphisms are unlikely to result in clinically significant changes in the anesthetic effect at the 0.4mg/kg dose in adults. Therefore, MIDD can indeed provide supportive information for dosing decisions and facilitate the efficient and effective development of HSK3486.

Metabolism characterization and chemical and plasma stability of casearin B and caseargrewiin F.

Oral preparations of Casearia sylvestris (guacatonga) are used as antacid, analgesic, anti-inflammatory and antiulcerogenic activities. The clerodane diterpenes casearin B (cas B) and caseargrewiin F (casg F) are major active compounds in vitro and in vivo. The oral bioavailability and metabolism of cas B and casg F were not previously investigated. We aimed to assess the stability of cas B and casg F in physiological conditions and their metabolism in human liver microsomes (HLM). The compounds were identified by UHPLC-QTOF-MS/MS and quantified by validated LC-MS methods. The stability of cas B and casg F in physiological conditions was assessed in vitro. Both diterpenes showed a fast degradation (p < 0.05) in simulated gastric fluid. Their metabolism is not mediated by cytochrome P-450 enzymes, but the depletion was inhibited by the esterase inhibitor NaF. Both diterpenes and their dialdehydes showed log P in the range of 3.6 to 4.0, suggesting high permeability. Metabolism kinetic data were fitted to the Michaelis-Menten profile with KM values of 61.4 μM and 66.4 μM and Vmax values of 327 and 648 nmol/min/mg of protein for cas B and casg F, respectively. Metabolism parameters in HLM were extrapolated to predict human hepatic clearance and suggest that casg F and cas B have a high hepatic extraction ratio. In conclusion, our data suggest that casg F and cas B present low oral bioavailability due to extensive gastric degradation and high hepatic extraction.

Development of a Fast and Sensitive UPLC–MS/MS Analytical Methodology for Fenebrutinib Estimation in Human Liver Microsomes: In Vitro and In Silico Metabolic Stability Evaluation

Fenebrutinib (GDC-0853; FNB) is an oral small molecule that was developed by Roche Pharmaceuticals to slow multiple sclerosis progression. FNB is a reversible bruton tyrosine kinase (BTK) inhibitor, which showed the maximum potency of BTK inhibitors in phase III clinical trials for multiple sclerosis. In the current study, a fast, specific, and sensitive UPLC-MS/MS method for FNB quantification in human liver microsomes (HLMs) was established with application to the evaluation of metabolic stability. The UPLC-MS/MS methodology was verified using the stated USFDA validation guidelines for bioanalytical methodologies that involve selectivity, linearity, accuracy and precision, carryover and extraction recovery, stability, and matrix effect. The FNB calibration curve displayed a linearity in the range from 1 ng/mL to 3000 ng/mL (y = 1.731x + 2.013; R2: 0.9954; RSD &lt; 4.37%) in the HLMs matrix. The limit of quantification was 0.88 ng/mL, which verified the UPLC-MS/MS analytical method sensitivity. The intraday and interday precision and accuracy results of the developed UPLC-MS/MS method were −3.99–14.0% and 0.52–3.83%, respectively. FNB and savolitinib (SVB) (internal standard) were chromatographically separated utilizing an isocratic mobile phase system with a ZORBAX Eclipse plus-C18 (50 mm, 2.1 mm, and 1.8 μm) column. The metabolic stability parameters for FNB, involving high intrinsic clearance (58.21 mL/min/kg) and a short in vitro half-life (13.93 min), revealed the high extraction ratio of FNB. Reviewing the literature revealed that the current UPLC-MS/MS method is the first analytical method for FNB quantification in the HLMs matrix with application to the assessment of FNB metabolic stability.

Systemic exposure of floxuridine after hepatic arterial infusion pump chemotherapy with floxuridine in patients with resected colorectal liver metastases

BackgroundFloxuridine’s high hepatic extraction ratio and short elimination half-life allows maximum liver exposure with minimal systemic side-effects. This study attempts to quantify the systemic exposure of floxuridine. MethodsPatients undergoing continuous hepatic arterial infusion pump (HAIP) floxuridine after resection of colorectal liver metastases (CRLM) in two centres underwent six cycles of floxuridine at start dose 0.12 mg/kg/day. No concomitant systemic chemotherapy was administered. Peripheral venous blood samples were drawn during the first two cycles: pre-dose (only in the second cycle), 30 min, 1 h, 2 h, 7 h, and 15 days after floxuridine infusion. Foxuridine concentration in the residual pump reservoir was measured on day 15 of both cycles. A floxuridine assay with a lower boundary of detection of 0.250 ng/mL was developed. Results265 blood samples were collected in the 25 patient included in this study. Floxuridine was mostly measurable at day 7 and day 15 (86 % and 88 % of patients respectively). The median dose corrected concentrations were 0.607 ng/mL [IQR: 0.472–0.747] for cycle 1 day 7, 0.579 ng/mL [IQR: 0.470–0.693] for cycle 1 day 15, 0.646 ng/mL [IQR: 0.463–0.8546] for cycle 2 day 7, and 0.534 ng/mL [IQR: 0.4257–0.7075] for cycle 2 day 15. One patient had remarkably high floxuridine concentrations reaching up to 44 ng/mL during the second cycle, without a clear explanation.The floxuridine concentration in the pump decreased by 14.7 % (range 0.5 %−37.8 %) over a period of 15 days (n = 18). ConclusionOverall, negligible systemic concentrations of floxuridine were detected. However, remarkably increased levels were detected in one patient. Floxuridine concentration in the pump decreases over time.

A Rapid and Sensitive UPLC-MS/MS Method for Quantifying Capmatinib in Human Liver Microsomes: Evaluation of Metabolic Stability by In Silico and In Vitro Analysis

Capmatinib (CMB) is an orally bioavailable mesenchymal–epithelial transition (MET) inhibitor approved by the US-FDA to treat metastatic non-small cell lung cancer (NSCLC) patients, with MET exon 14 skipping mutation. The current study aimed to establish a specific, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analytical method for quantifying CMB in human liver microsomes (HLMs), with therapeutic implications for assessing metabolic stability. Validation of the UPLC-MS/MS analytical method in the HLMs was performed using selectivity, sensitivity, linearity, accuracy, precision, extraction recovery, stability, and matrix effects according to the guidelines for bio-analytical method validation of the US-FDA. CMB was ionized by positive electrospray ionization (ESI) as the ionization source and analysed using multiple reaction monitoring (MRM) as the mass analyser mode. CMB and pemigatinib (PMT) were resolved on the C18 column, with an isocratic mobile phase. The CMB calibration curve showed linearity in the concentration range of 1–3000 ng/mL. The intra- and inter-day accuracy and precision were −7.67–4.48% and 0.46–6.99%, respectively. The lower limit of quantification (LLOQ) of 0.94 ng/mL confirmed the sensitivity of the UPLC-MS/MS analytical method. The intrinsic clearance (Clint) and in vitro half-life (t1/2) of CMB were 61.85 mL/min/kg and 13.11 min, respectively. CMB showed a high extraction ratio. The present study is the first to develop, establish, and standardize UPLC-MS/MS for the purpose of quantifying and evaluating the metabolic stability of CMB.

Performance analysis of multi-well EGS system based on unique network structure — Voronoi fractures

Fracture network is an important factor in the utilization of geothermal energy, its composition and structure have an important influence on the development of geothermal energy. As a component of EGS system, fractures have various forms. Therefore, this paper studies the influence of fracture morphology on reservoir heat extraction. The Voronoi is used to describe the unique network structure and is applied to geothermal development system as a form of fracture network. Therefore, a THM coupled EGS model with Voronoi fractures is established to observe its thermal extraction performance. In present work, the effects of fracture block numbers, well length, well spacing, injection mass flow rate and injection temperature on the thermal extraction performance of EGS system are numerically investigated. The results show that the model has higher production temperature when the number of Voronoi blocks is 77, and the production temperature in the 30th year is 494.01 K. The influence of the change of well spacing on the production temperature of the model is more obvious than that of the change of well length. At the same time, the longer the well length, the smaller the injection pressure, the stronger the connectivity between the injection and production wells, and the narrower the end of the injection well in the temperature diagram. Furthermore, the increase of injection mass flow rate reduces the production temperature of the model, when the injection mass flow rate increases from 80 kg/s to 140 kg/s, the production temperature decreases from 494.01 K to 450.99 K. However, because the increase of the total injection mass flow rate, the large mass flow rate still has a high heat extraction ratio. The higher the injection temperature is, the smaller the pressure difference between injection wells and production wells is. The temperature changes the permeability and liquid viscosity of the reservoir, thereby reducing the pressure difference. In addition, with the increase of injection wells, the production temperature of the model increases, and the injection pressure decreases. However, the pressure difference between injection wells and production wells increases, indicating that the pressure of production wells is large, so the production cost increases. Therefore, in the actual production situation, reasonable selection of geothermal operation parameters should consider the operation cost and the difficulty of development.

Insight into the oxidation mechanisms of vanadium slag and its application in the separation of V and Cr

Vanadium slag contains valuable element vanadium and heavy metal element chromium. V and Cr in the traditional oxidation roasting process were simultaneously oxidized by oxidant O2 in the air, which made the separation of V and Cr difficult, and produced highly toxic Cr6+ that polluted seriously the environment. The valence states of Fe, Cr and V in vanadium slag increased during oxidation roasting. In order to reveal the oxidation mechanisms, the oxidative roasting of Na2CO3–Cr2O3, Na2CO3–FeCr2O4 and Na2CO3–V2O3 was investigated. The results showed that Cr2O3 could be oxidized by O2 and the presence of Fe2+ reduced the oxidation ratio of Cr3+. Moreover, it was found for the first time that the V3+ could be oxidized by CO2. The calculation of FactSage 8.0 showed that V2O3 could be oxidized by Na2CO3. However, V2O3 could not be directly oxidized to VO2 or V2O5 by CO2. Due to the lack of NaVO2 data in the thermodynamic database, the reaction of NaVO2 and CO2 was firstly simulated by Vienna ab initio simulation package (VASP). The results indicated that NaVO2 could be oxidized by CO2. On the basis of revealing the oxidation mechanisms of V, Cr, and Fe, an innovative method for selective oxidation of vanadium by oxidant CO2 was proposed. The extraction ratio of vanadium could reach 90.5% at 800 °C, in which the mass ratio of V/Cr was 32,400. Mass ratio of V/Cr in this work was 1448 to 20,250 times larger than that in the literatures. Based on the high vanadium extraction ratio, the problems of separation of V and Cr and the presence of Cr6+ were solved from the source. This novel discovery may provide an inspiration for the vanadium metallurgical revolutionary.

Comparative Study of the Efficiency of Additives in the Extraction of Phycocyanin-C from Arthrospira maxima Using Ultrasonication

Several phycocyanin extraction methods have been proposed, however, most of them present economical or productive barriers. One of the most promising methods that has been suggested is ultrasonication. We have analyzed here the effect of operational conditions and additives on the extraction and purity of phycocyanin from Arthrospira maxima. We followed three experimental designs to determine the best combination of buffered pH solutions, additives, fresh and lyophilized biomass. We have found that additives such as citric acid and/or disaccharides could be beneficial to the extraction process. We concluded that the biomass-solvent ratio is a determining factor to obtain high extraction and purity ratios with short ultrasonication times.

Ammonia leaching process for selective extraction of nickel and cobalt from polymetallic mixed hydroxide precipitate

Nitric acid pressure leaching process (NAPL) uses nitric acid as the leaching medium to produce cobalt and nickel raw materials. Based on the benefits of nitric acid pressure leaching process for laterite ore, this paper proposes a process of "nitric acid pressure leaching-neutralization precipitation-reductive ammonia leaching separation". Firstly, thermodynamic analysis confirmed the possibilities of nickel and cobalt leaching from ammonia solution. Then the impacts of leaching agent composition, temperature, time, and liquid-solid ratio on nickel and cobalt extraction ratios were investigated. Finally, the leaching behaviors of nickel and cobalt during ammonia leaching were investigated using the shrinking core model. In addition, the phase and morphology of the leach residue were studied using X-ray diffraction (XRD) and scanning electron microscope/energy dispersive spectrometer (SEM/EDS). The reductive ammonia leaching method for treating MHP results in high nickel and cobalt extraction ratios, good separation results, and recyclable material, all of which have significant industrial application value.

Assessing Liver-to-Plasma Partition Coefficients and In Silico Calculation Methods: When Does the Hepatic Model Matter in PBPK?

The primary models used in pharmacokinetics (PK) to assess hepatic clearance (CLh ) are the well-stirred (WSM), parallel tube (PTM), and dispersion model (DM) that differ in their internal flow patterns and assumed unbound liver concentrations. Physiologically-Based Pharmacokinetic (PBPK) models require a hepatic intrinsic clearance (CLint ) and tissue-to-plasma partition coefficient (Kp ). Given measured systemic and liver concentration-time profiles, these hepatic models perform similarly but yield model-specific CLint and Kp estimates. This work provides mathematical relationships for the three basic hepatic models and assesses their corresponding PBPK-relevant Kp values with literature-reported single-dose blood and liver concentration-time data of 14 compounds. Model fittings were performed with an open-loop approach where the CLh and extraction ratio (ER) were first estimated from fitting the blood data yielding CLint values for the three hepatic models. The pre-fitted blood data served as forcing input functions to obtain PBPK-operative Kp estimates that were compared with those obtained by the tissue/plasma area ratio (AR), Chen & Gross (C&G) and published in silico methods. The CLint and Kp values for the hepatic models increased with the ER and both showed a rank order being WSM > DM > PTM. Drugs with low ER showed no differences as expected. With model-specific CLint and Kp values, all hepatic models predict the same steady-state Kp (Kp ss ) that is comparable to those from the AR and C&G methods and reported by direct measurement. All in silico methods performed poorly for most compounds. Hepatic model selection requires cautious application and interpretation in PBPK modeling. Significance Statement The three hepatic models generate different single-dose (non-steady-state) values of CLint and Kp in PBPK models especially for drugs with high ER; however, all Kp ss values expected from constant rate infusion studies were the same. These findings are relevant when using these models for IVIVE where a model-dependent CLint is used to correct measured tissue concentrations for depletion by metabolism. This model-dependency may also have an impact when assessing the PK/pharmacodynamic relationships when effects relate to assumed hepatic concentrations.

This Month in Anesthesiology

This Month in Anesthesiology

This Month in Anesthesiology

This Month in Anesthesiology

What Do We Know About Remdesivir Drug Interactions?

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS‐Co‐V‐2) has resulted in a critical need to rapidly develop new pharmacologic interventions and disseminate information. This has led to confusing and conflicting information on drug efficacy. Remdesivir has emerged as a promising treatment for SARS‐Co‐V‐2 infection yet published clinical pharmacology and drug interaction studies are limited. Additional studies of the disposition of remdesivir, its active metabolite (GS‐441524), and its triphosphate metabolite (GS‐443902) are needed.

Total, renal and hepatic clearances of doxorubicin and formation clearance of doxorubicinol in patients with breast cancer: Estimation of doxorubicin hepatic extraction ratio

Doxorubicin (DOX) is a cytotoxic drug which has remained as an essential component of chemotherapy regiment for breast cancer. The cardiotoxicity of DOX is related to the accumulation of its main metabolite doxorubicinol (DOXOL) in the cardiac tissue. Although the pharmacokinetics of DOX shows high interindividual variability, there are no significant covariates to improve dose adjustment. The present study reports the pharmacokinetics of both DOX and DOXOL in a homogeneous population of young female patients with breast cancer (n = 12) making use of a standardized drug association, evaluated in the very first chemotherapy cycle, using plasma and urine data that allowed the calculation of the renal clearance of DOX, the formation clearance of DOXOL and the hepatic clearance of DOX. The extensive data availability also made it possible to estimate the hepatic extraction ratio of DOX for the investigated population, as well as to determine DOXOL unbound fraction in plasma for the first time in humans. DOX and DOXOL simultaneous analysis in plasma, plasma ultrafiltrate, and urine were performed by liquid chromatography coupled to mass spectrometry (LC–MS/MS). The pharmacokinetics profile of both DOX and DOXOL showed high variability (geometric coefficient of variation of area under the plasma concentration versus time curve extrapolated to infinity was approximately 215 %). The geometrics means were 0.26 for DOXOL/DOX AUC ratio, 15 % and 17 % for unbound fractions of DOX and DOXOL, respectively, 30.70 L⋅h−1 for total clearance, 0.66 L⋅h−1 for renal clearance, 29.97 L⋅h−1 for hepatic clearance and 0.39 L⋅h−1 for the formation clearance of the metabolite DOXOL. The 95 % confidence interval of the estimated hepatic extraction ratio of DOX ranged from 0.14 to 0.79, which characterizes DOX as a drug of low, intermediate or high hepatic extraction ratio.