Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.

1992 ◽  
Vol 10 (6) ◽  
pp. 995-1000 ◽  
Author(s):  
L J Ayash ◽  
J E Wright ◽  
O Tretyakov ◽  
R Gonin ◽  
A Elias ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Tumor Response ◽  
Parent Compound ◽  
Autologous Bone Marrow Transplantation ◽  
Metastatic Breast ◽  
Subsequent Development ◽  
Biologically Active ◽  
Pharmacokinetic Data ◽  
Active Metabolites ◽  
Metastatic Breast Carcinoma

BACKGROUND Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction. PATIENTS AND METHODS Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available. RESULTS Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008). CONCLUSION These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.

scholarly journals In Vitro–In Vivo Correlations Based on In Vitro Dissolution of Parent Drug Diltiazem and Pharmacokinetics of its Metabolite

Pharmaceutics ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 344 ◽  
Author(s):  
Mircioiu ◽  
Anuta ◽  
Mircioiu ◽  
Nicolescu ◽  
Fotaki
Keyword(s):  
Parent Compound ◽  
Parent Drug ◽  
Type Equation ◽  
Drug Dissolution ◽  
In Vitro Dissolution ◽  
Pharmacokinetic Data ◽  
Active Metabolites ◽  
In Vitro Data

In this study a novel type of in vitro–in vivo correlation (IVIVC) is proposed: The correlation of the in vitro parent drug dissolution data with the in vivo pharmacokinetic data of drug’s metabolite after the oral administration of the parent drug. The pharmacokinetic data for the parent drug diltiazem (DTZ) and its desacetyl diltiazem metabolite (DTZM) were obtained from an in vivo study performed in 19 healthy volunteers. The pharmacokinetics of the parent drug and its metabolite followed a pseudomono-compartmental model and deconvolution of the DTZ or DTZM plasma concentration profiles was performed with a Wagner–Nelson-type equation. The calculated in vivo absorption fractions were correlated with the in vitro DTZ dissolution data obtained with USP 2 apparatus. A linear IVIVC was obtained for both DTZ and DTZM, with a better correlation observed for the case of the metabolite. This type of correlation of the in vitro data of the parent compound with the in vivo data of the metabolite could be useful for the development of drugs with active metabolites and prodrugs.

Long-term Survival After Autologous Bone Marrow Transplantation for Metastatic Breast Carcinoma

1995 ◽  
Vol 88 (3) ◽  
pp. 320-326 ◽  
Author(s):  
RUBEN A. SAEZ ◽  
R. BRADLEY SLEASE ◽  
GEORGE B. SELBY ◽  
CHARLES STRNAD ◽  
ROBERT B. EPSTEIN ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Breast Carcinoma ◽  
Autologous Bone Marrow Transplantation ◽  
Metastatic Breast ◽  
Autologous Bone Marrow ◽  
Term Survival ◽  
Metastatic Breast Carcinoma ◽  
Autologous Bone

Bioavailability of naringenin chalcone in humans after ingestion of cherry tomatoes

2020 ◽  
Vol 90 (5-6) ◽  
pp. 411-416 ◽  
Author(s):  
Carina Kolot ◽  
Ana Rodriguez-Mateos ◽  
Rodrigo Feliciano ◽  
Katharina Bottermann ◽  
Wilhelm Stahl
Keyword(s):  
Plasma Levels ◽  
Average Concentration ◽  
Biologically Active ◽  
Thiol Groups ◽  
Structural Element ◽  
Active Molecule ◽  
Reactive Center ◽  
Average Maximum ◽  
Alpha Beta ◽  
Cherry Tomatoes

Abstract. Chalcones are a type of flavonoids characterized by an α-β unsaturated structural element which may react with thiol groups to activate pathways such as the Nrf2-Keap-1 system. Naringenin chalcone is abundant in the diet but little is known about its bioavailability. In this work, the bioavailability of naringenin chalcone from tomatoes was investigated in a group of healthy men (n=10). After ingestion of 600 grams of tomatoes providing a single dose of 17.3 mg naringenin chalcone, 0.2 mg of naringenin, and 195 mg naringin plasma levels of free and conjugated naringenin and naringenin chalcone (glucuronide and sulfate) were analyzed by UHPLC-QTOF-MS at 0.5, 1, 3, and 6 h post-consumption. Plasma levels of conjugated naringenin increased to about 12 nmol/L with a maximum at about 3 h. Concentrations of free naringenin hardly elevated above baseline. Plasma levels of free and conjugated naringenin chalcone significantly increased. A maximum of the conjugated chalcone was reached at about 3 h after ingestion with an average concentration of about 0.5 nmol/L. No free chalcone was detectable at baseline but low amounts of the unconjugated compound could be detected with an average maximum of 0.8 nmol/L at about 1 h after ingestion. The data demonstrate that naringenin chalcone is bioavailable in humans from cherry tomatoes as a dietary source. However, availability is poor and intramolecular cyclisation as well as extended metabolism likely contribute to the inactivation of the reactive alpha-beta unsaturated reactive center as well as the excretion of the biologically active molecule, respectively.

Metabolomics of Healthy Berry Fruits

2019 ◽  
Vol 25 (37) ◽  
pp. 4888-4902 ◽  
Author(s):  
Gilda D'Urso ◽  
Sonia Piacente ◽  
Cosimo Pizza ◽  
Paola Montoro
Keyword(s):  
Biological Activities ◽  
Biologically Active ◽  
In Vivo Studies ◽  
Bioactive Metabolites ◽  
Active Metabolites ◽  
Positive Effects ◽  
Cell Functions ◽  
Berry Fruits

The consumption of berry-type fruits has become very popular in recent years because of their positive effects on human health. Berries are in fact widely known for their health-promoting benefits, including prevention of chronic disease, cardiovascular disease and cancer. Berries are a rich source of bioactive metabolites, such as vitamins, minerals, and phenolic compounds, mainly anthocyanins. Numerous in vitro and in vivo studies recognized the health effects of berries and their function as bioactive modulators of various cell functions associated with oxidative stress. Plants have one of the largest metabolome databases, with over 1200 papers on plant metabolomics published only in the last decade. Mass spectrometry (MS) and NMR (Nuclear Magnetic Resonance) are the most important analytical technologies on which the emerging ''omics'' approaches are based. They may provide detection and quantization of thousands of biologically active metabolites from a tissue, working in a ''global'' or ''targeted'' manner, down to ultra-trace levels. In the present review, we highlighted the use of MS and NMR-based strategies and Multivariate Data Analysis for the valorization of berries known for their biological activities, important as food and often used in the preparation of nutraceutical formulations.

Spices with Breast Cancer Chemopreventive and Therapeutic Potentials: A Functional Foods Based-Review

2018 ◽  
Vol 18 (2) ◽  
pp. 182-194 ◽  
Author(s):  
Aliyu Muhammad ◽  
Mohammed Auwal Ibrahim ◽  
Ochuko Lucky Erukainure ◽  
Ibrahim Malami ◽  
Auwal Adamu
Keyword(s):  
Breast Cancer ◽  
Urban Areas ◽  
Cancer Chemoprevention ◽  
Biologically Active ◽  
Active Metabolites ◽  
Rural And Urban Areas ◽  
Anticancer Properties ◽  
Rural And Urban ◽  
Breast Cancer Chemoprevention ◽  
Biologically Active Metabolites

Background: Cancer is a multifaceted metabolic disease that affects sizeable dwellers of rural and urban areas. Among the various types of cancer, mammary cancer is one of the most frequently diagnosed cancers in women. Its menace can be curbed with locally consumed spices due to their multiple bioactive phytochemicals. Aims: This review focuses on the breast cancer chemopreventive and therapeutic potentials of locally consumed spices. Methods/Results: The most commonly consumed spices with breast cancer chemopreventive and chemotherapeutic phytochemical include pepper, onions, ginger, garlic, curry and thyme containing many biologically active metabolites ranging from vitamins, fatty acids esters, polyphenols/phenolics, sulfurcontaining compounds and anthraquinones with proven antioxidant, anti-inflammatory, immuno-modulatory, antitumor and anticancer properties against breast cancer/carcinogenesis. Therefore, extracts and active principles of these spices could be explored in breast cancer chemoprevention and possibly therapeutically which may provide an avenue for reducing the risk and prevalence of breast cancer.

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