Disposition of bepridil in laboratory animals and man

Wu, W. N.; Pritchard, J. Frederick; Ng, K.T.; Hills, J F; Uetz, Janet A.; Yorgey, K A; McKown, Linda A.; O’Neill, Patrick J.

doi:10.3109/00498259209046614

Cited by 17 publications

(6 citation statements)

References 6 publications

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“…This proposal has experimental support [ 10, 32,33]. Since bepridil can inhibit the channel at micromolar levels, and it has a long half-life of 48 hr in humans [9,34], a test of its ability to suppress the formation of irreversible sickle cells may be warranted.…”

Section: Discussionmentioning

confidence: 99%

Bepridil as an antisickling agent: Membrane internalization and cell rigidity

Johnson

Acquaye

Féo³

et al. 1994

American J Hematol

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The calcium channel antagonist, bepridil, beta-(2-methylpropoxy)methyl-N-phenyl-N-(phenylmethyl)-1-pyrrol idineethanamine monochloride monohydrate, inhibits the sickling of deoxygenated sickle (SS) erythrocytes, as determined by light microscopy. The anti-sickling effect was seen only in dilute suspensions of red cells. In concentrated erythrocyte suspensions, sickling was not inhibited and measurements of hematocrit and cell density were unchanged by bepridil. The determination of cell volume in dilute suspensions was complicated by bepridil's tendency to aggregate, but rapid measurements by electronic sizing also indicated no increase in cell volume, up to a bepridil concentration of 200 microM. Ektacytometry of dilute sickle cell suspensions suggested an explanation for the anti-sickling action of bepridil. Osmotic scan ektacytometry disclosed that bepridil initially increased the surface area of the red cell, as shown by a shift in the low osmolality minimum. This change was complete in 10 sec, the shortest time that could be measured. Subsequently, at concentrations that were observed to inhibit the sickling of deoxygenated sickle cells (100 microM or greater), red cells underwent a loss in surface area that was complete in 1 min. There was a concomitant loss of cell deformability. Light and scanning electron microscopy has previously shown that bepridil is a stomatocytic agent. Using transmission electron microscopy, we verified that the loss of surface area was a consequence of endocytosis, presumably as the end stage of the stomatocytic transformation induced by bepridil. Bepridil did not inhibit intracellular hemoglobin S polymerization even at 200 microM, as shown by oxygen scan ektacytometry. Bepridil thus appears to inhibit the sickling of deoxygenated SS cells by inducing endocytosis and lowering cell deformability. This mechanism may explain the anti-sickling effect of other basic amphiphiles, such as chlorpromazine.

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Section: Discussionmentioning

confidence: 99%

Bepridil as an antisickling agent: Membrane internalization and cell rigidity

Johnson

Acquaye

Féo³

et al. 1994

American J Hematol

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“…Similar ring-opening metabolites at the pyrrolidine ring have been identified in a variety of studies, such as in levormeloxifene (Mountfield et al, 2000), bepridil (Wu et al, 1992), and prolintane (Rucker et al, 1992). It is proposed that the ring-opening metabolites are formed through alicyclic hydroxylation at the ␣-C of the pyrrolidine ring (Wu et al, 1988). The absolute structural assignments of M2 through M4 require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Pharmacokinetics of a Novel Src Kinase Inhibitor TG100435 ([7-(2,6-Dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine) and Its Active N-Oxide Metabolite TG100855 ([7-(2,6-Dichloro-phenyl)-5-methylbenzo[1,2,4]triazin-3-yl]-{4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenyl}-amine)

Hu¹,

Söll²,

Yee³

et al. 2007

Drug Metabolism and Disposition

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TG100855 is 2 to 9 times more potent than the parent compound. Flavin-containing monooxygenases are the primary enzymes mediating the biotransformation. Significant conversion of TG100435 to TG100855 has been observed in rat and dog after oral administration. Systemic exposure of TG100855 is 1.1-and 2.1-fold greater than that of TG100435 in rat and dog after oral dosing of TG100435. Since TG100435 is predominantly converted to the more potent N-oxide metabolite across species in vivo and in vitro, the overall tyrosine kinase inhibition in animal models may be substantially increased after oral administration of TG100435.The Src kinase family consists of a group of nonreceptor protein tyrosine kinases (PTKs) including Src, Yes, Fyn, Lyn, Hck, Blk, Brk, Fgr, Frk, Srm, Lck, and Yrk (Trevino et al., 2006). Src PTKs play critical roles in a variety of cellular signal transduction pathways regulating diverse processes including cell survival, proliferation, motility, adhesion, and transformation. Elevated or constitutive activation of Src kinase is commonly observed in tumors, most notably in colon and breast cancer, but also occurs in other tumor types, including pancreatic cancer (Lutz et al., 1998). Overexpression of Src PTKs has been associated with tumorigenesis, metastasis, and invasion; consequently, Src family kinases have become very important biological targets in oncological drug development. Small molecule kinase inhibitors have shown great promise as a new class of therapeutics. Most small molecule kinase inhibitors bind at the ATP-binding site and exhibit much less toxicity than currently used chemotherapeutic agents (Levitzki and Mishani, 2006).Nitrogen-containing small molecules are the most common of all of the organic compounds of pharmacological interest. The functionalities of nitrogen provide flexibility in the drug design toward proper potencies and physical properties. However, the multiple oxidation states of nitrogen increase the metabolic instability of drug candidates (Cho and Lindeke, 1988). N-Oxidation is a common biotransformation of aliphatic tertiary amine-containing compounds. The pharmacological and toxicological importance of this metabolic pathway has been widely studied. The nitrogen-centered oxidation of tertiary amine drugs is commonly considered as a detoxification pathway resulting in nontoxic and biologically inactive metabolites (Carmella et al., 1997;Cashman and Zhang, 2006;Krueger et al., 2006). The benign nature of tertiary amine N-oxides under normal physiological conditions has been used as a prodrug approach to selectively elicit cytotoxic events associated with hypoxic conditions in solid tumor

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“…Mean bepridil PK data were extracted from Reference [35] using WebPlotDigitizer (WebPlotDigitizer -Extract data from plots, images, and maps), where 5 healthy male volunteers (20 ~ 49 years old) were administered 400 mg bepridil-HCl orally. Mean toremifene PK data were extracted from reference [36] using the same extraction method, where volunteers were orally administered 50 mg (n = 3) and 100 mg (n = 3) toremifene.…”

Section: Mathematical Modeling Studies 251 Human Pharmacokinetic Datamentioning

confidence: 99%

“…Bepridil: The aim is to achieve a Cmax of ~4 μM (average IC50, Supplemental Table 5) to yield >/~50% survival. An oral dose (PO) of 150 mg/kg yielded a Cmax of 1.5 μM [35]. Hence 2.67-fold (4/1.5) more bepridil would be needed, suggesting a top oral dose of 400 mg/kg.…”

Section: Selection Of Drug Doses For Combination Tests In Micementioning

confidence: 99%

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Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs Against Ebola Virus In Vivo

Finch¹,

Dyall²,

Xu³

et al. 2021

Preprint

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Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

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Disposition of bepridil in laboratory animals and man

Cited by 17 publications

References 6 publications

Bepridil as an antisickling agent: Membrane internalization and cell rigidity

Bepridil as an antisickling agent: Membrane internalization and cell rigidity

Formulation, Stability, Pharmacokinetic, and Modeling Studies for Tests of Synergistic Combinations of Orally Available Approved Drugs Against Ebola Virus In Vivo

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