In Vivo Red Blood Cells/Plasma Partition Coefficient of Treosulfan and Its Active Monoepoxide in Rats

Romański, Michał; Zacharzewska, Anna; Tężyk, Artur; Główka, Franciszek

doi:10.1007/s13318-018-0469-7

Cited by 8 publications

(5 citation statements)

References 32 publications

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“…Based on the previous study, BBR could bind to the plasma and the free drug molecules in plasma partition into erythrocyte (Romański et al., 2018 ; Chen et al., 2021 ). Therefore, the erythrocytes/plasma partition coefficient ( C e/p ) value was calculated as the ratio of the total concentration of BBR in the erythrocyte lysate ( C e ) and plasma ( C p ).…”

Section: Resultsmentioning

confidence: 99%

The discovery of berberine erythrocyte-hemoglobin self-assembly delivery system: a neglected carrier underlying its pharmacokinetics

Chen

et al. 2022

Drug Delivery

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Berberine (BBR) has extremely low concentration and high tissue distribution. However, current pharmacokinetic studies predominantly focus on its concentration in plasma, which could hardly make a comprehensive understanding of its pharmacokinetic process. This study made a pioneering endeavor to explore the erythrocyte-hemoglobin (Hb) self-assembly system of BBR by exploring the interaction of BBR with erythrocyte and the combination of BBR with Hb. Results showed that BBR had a low bioavailability ( C 0 = 2.833 μg/mL via intravenous administration of 2.5 mg/kg BBR and C max = 0.260 μg/mL via oral administration of 400 mg/kg BBR). Besides, BBR achieved higher concentrations in erythrocytes than plasma, and the erythrocytes count and Hb content were significantly decreased after intravenous administration. Hemolysis rate indicated the BBR-erythrocyte system (with 2% erythrocytes) was relatively stable without hemolysis at the concentration of 1.00 mg/mL. And the maximum percentage of drug loading was 100% when the BBR-erythrocyte concentration was 0.185 μg/mL. Furthermore, incubation of BBR and erythrocytes resulted in internalization of the erythrocyte membrane and the formation of intracellular vacuoles. The thermodynamic parameters indicated that the binding process of bovine hemoglobin (BHB) and BBR was spontaneous. UV-vis absorption spectra, synchronous fluorescence, circular dichroism and Raman spectra collectively indicated that BBR showed strong binding affinity toward BHB and affected the molecular environment of residues like tryptophan and tyrosine in BHB, resulting in the conformational changes of its secondary and tertiary structure. Molecular docking indicated BBR interacted with Arg-141 residue of BHB via hydrogen bond with the bond length of 2.55 Å. The ΔG value of the BHB-BBR system was −31.79 kJ/mol. Molecular dynamics simulation indicated the root mean square derivation of BBR-BHB was <0.025 nm, suggestive of stable conformation. Cumulatively, there was an erythrocyte-Hb self-assembled drug delivery system after oral or intravenous administration of BBR, which conceivably gained novel insight into the discrepancy between the extremely low plasma concentration and relatively high tissue concentration of BBR.

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Section: Resultsmentioning

confidence: 99%

The discovery of berberine erythrocyte-hemoglobin self-assembly delivery system: a neglected carrier underlying its pharmacokinetics

Chen

et al. 2022

Drug Delivery

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“…A major role of EBDM in treosulfan-dependent DNA cross-linking would allow reconciling of the anticancer and myeloablative properties of the prodrug with the bioanalytical data on its epoxides: immeasurable levels of DEB in human and animal tissues after administration of treosulfan, and micromolar concentrations of EBDM found in human and animal plasma, and also in animal tissues, including bone marrow, liver, lungs, brain, cerebrospinal fluid, kidneys, and muscles. [22][23][24][25]28,35,36 5. CONCLUSION In this work, the kinetics of DNA alkylation at the N-7 guanine by the two biologically active epoxides of the prodrug treosulfan, EBDM and DEB, was investigated for the first time.…”

Section: Discussionmentioning

confidence: 99%

“…Some of these lesions are more hydrolytically stable in DNA than bis-N7G-BD, and probably contribute to biological effects of DNA alkylation. , As EBDM, via HMSBG, is supposed to produce greater amounts of EHBG than DEB in treosulfan-treated patients, the former may be also expected to induce higher number of guanine–adenine cross-links. A major role of EBDM in treosulfan-dependent DNA cross-linking would allow reconciling of the anticancer and myeloablative properties of the prodrug with the bioanalytical data on its epoxides: immeasurable levels of DEB in human and animal tissues after administration of treosulfan, and micromolar concentrations of EBDM found in human and animal plasma, and also in animal tissues, including bone marrow, liver, lungs, brain, cerebrospinal fluid, kidneys, and muscles. − ,,, …”

Section: Discussionmentioning

confidence: 99%

Kinetics of in Vitro Guanine-N7-Alkylation in Calf Thymus DNA by (2S,3S)-1,2-Epoxybutane-3,4-diol 4-methanesulfonate and (2S,3S)-1,2:3,4-Diepoxybutane: Revision of the Mechanism of DNA Cross-Linking by the Prodrug Treosulfan

2019

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Prodrug treosulfan, originally registered for treatment of ovarian cancer, has gained a use in conditioning prior to hematopoietic stem cell transplantation. Treosulfan converts nonenzymatically to the monoepoxide intermediate (EBDM), and then to (2S,3S)-1,2:3,4-diepoxybutane (DEB). The latter alkylates DNA forming mainly (2′S,3′S)-N-7-(2′,3′,4′-trihydroxybut-1′-yl)guanine (THBG) and (2S,3S)-1,4-bis(guan-7′-yl)butane-2,3-diol cross-link (bis-N7G-BD) via the intermediate epoxide adduct (EHBG). It is believed that DNA cross-linking by DEB is a primary mechanism for the anticancer and myeloablative properties of treosulfan, but clear evidence is lacking. Recently, we have proved that EBDM alkylates DNA producing (2′S,3′S)-N-7-(2′,3′-dihydroxy-4′-methylsulfonyloxybut-1′-yl)-guanine (HMSBG) and that free HMSBG converts to EHBG. In this paper, we investigated the kinetics of HMSBG, bis-N7G-BD, and THBG in DNA in vitro to elucidate the contribution of EBDM and DEB to treosulfan-dependent DNA–DNA cross-linking. Calf thymus DNA was exposed to (A) 100 μM treosulfan, (B) 200 μM treosulfan, and (C) DEB at a concentration 100 μM, exceeding that produced by 200 μM treosulfan. Following mild acid thermal hydrolysis of DNA, ultrafiltration, and off-line HPLC purification, the guanine adducts were quantified by LC–MS/MS. Both bis-N7G-BD and THBG reached highest concentrations in the DNA in experiment B. Ratios of the maximal concentration of bis-N7G-BD and THBG to DEB (adduct C max/DEB C max) in experiments A and B were 1.7–3.0-times greater than in experiment C. EHBG converted to the bis-N7G-BD cross-link at a much higher rate constant (0.20 h–1) than EBDM and DEB initially alkylated the DNA (1.8–3.4 × 10–5 h–1), giving rise to HMSBG and EHBG, respectively. HMSBG decayed unexpectedly slowly (0.022 h–1) compared with the previously reported behavior of the free adduct (0.14 h–1), which revealed the inhibitory effect of the DNA environment on the adduct epoxidation to EHBG. A kinetic simulation based on the obtained results and the literature pharmacokinetic parameters of treosulfan, EBDM, and DEB suggested that in patients treated with the prodrug, EBDM could produce the vast majority of EHBG and bis-N7G-BD via HMSBG. In conclusion, EBDM can produce DNA–DNA lesions independently of DEB, and likely plays a greater role in DNA cross-linking after in vivo administration of treosulfan than DEB. These findings compel revision of the previously proposed mechanism of the pharmacological action of treosulfan and contribute to better understanding of the importance of EBDM for biological effects.

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“…Blood plasma partitioning: Enables the understanding of the distribution of a compound between blood cells and plasma. [41] 3. Brain tissue binding: Plasma protein binding assay is not suitable to measure drug penetration to the brain because the composition of the brain and plasma are different.…”

Section: A Perspective View Of the Characteristics And Qualification Of In Vitro Human Relevant Adme Systems On A Chipmentioning

confidence: 99%

“…Blood plasma partitioning: Enables the understanding of the distribution of a compound between blood cells and plasma. [ 41 ]…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics‐On‐a‐Chip: In Vitro Microphysiological Models for Emulating of Drugs ADME

et al. 2021

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pharmacodynamics (PD), and toxicity studies, of the past century and continue to provide a wealth of knowledge and understanding of various diseases mechanism and therapy. [1][2][3] However, the use of these models in research and industrial applications has been a subject of heated debate, particularly, due to ethical matters and the increasing pressure by the animalright activists. [4] In addition, the phylogenetic difference between laboratory animals and humans may lead to drug failure during human clinical studies. [5] Furthermore, the inherent complexity of the animal's body tissue makes it difficult to interpret the physiological events that characterize the interaction of a particular organ or cells with exogenic factors. [6] In line with regulatory developments precluding the use of animal testing, human in vitro methodologies is required to replace the animal-based testes while permitting equivalent or superior prediction. [7,8] Despite many efforts, no sufficiently acceptable in vitro approaches have been developed to date, and the major gap to predict drug response in human still existed. Utilizing animal models can lead to significant insights into the complex pathophysiology of the disease. [9] However, the pathophysiology may differ between humans and animals. [10,11] Comparing to animal model-based studies, these interactions are less well understood in humans. This is a necessity considering the differences between animal and human immune responses and outcomes in preclinical models versus clinical trials. [10,11] There is consequently a real need for in vitro models of the human organs that closely mimic the physiological processes of disease development with an acceptable level of flexibility, accuracy, and reproducibility for efficient screening of potential drug candidates. Such models would increase the predictability of human response to drugs and reduce experimentation expenses and speed up the screening processes. Failing to produce safe and efficient preclinical leads and drug candidates is associated with overall low R&D efficiency and high cost. The cost of developing a new drug that gains marketing approval is estimated to be $2.6 billion (as of 2013) which includes the in vitro and in vivo animal models during the preclinical and clinical trials stages which may last several Despite many ongoing efforts across the full spectrum of pharmaceutical and biotech industries, drug development is still a costly undertaking that involves a high risk of failure during clinical trials. Animal models played vital roles in understanding the mechanism of human diseases. However, the use of these models has been a subject of heated debate, particularly due to ethical matters and the inevitable pathophysiological differences between animals and humans. Current in vitro models lack the sufficient functionality and predictivity of human pharmacokinetics and toxicity, therefore, are not capable to fully replace animal models. The recent development of microphysiological systems has shown great potentia...

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In Vivo Red Blood Cells/Plasma Partition Coefficient of Treosulfan and Its Active Monoepoxide in Rats

Cited by 8 publications

References 32 publications

The discovery of berberine erythrocyte-hemoglobin self-assembly delivery system: a neglected carrier underlying its pharmacokinetics

The discovery of berberine erythrocyte-hemoglobin self-assembly delivery system: a neglected carrier underlying its pharmacokinetics

Kinetics of in Vitro Guanine-N7-Alkylation in Calf Thymus DNA by (2S,3S)-1,2-Epoxybutane-3,4-diol 4-methanesulfonate and (2S,3S)-1,2:3,4-Diepoxybutane: Revision of the Mechanism of DNA Cross-Linking by the Prodrug Treosulfan

Pharmacokinetics‐On‐a‐Chip: In Vitro Microphysiological Models for Emulating of Drugs ADME

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