Pharmacokinetics of toremifene

Anttila, Markku; Valavaara, Ritva; Kivinen, Seppo; Mäenpää, Juhani

doi:10.1016/0022-4731(90)90019-o

Cited by 55 publications

(32 citation statements)

References 3 publications

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“…Therapeutic doses of tamoxifen (20-40 mg/day) cause about 0.5 pM serum concentration (Lien et al 1991). The 60 mg/day dose of toremifene produces about 2 pM serum concentration (Anttila et al 1990). High doses of tamoxifen can produce serum concentrations of up to 3.5 pM (Stuart et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Effects of Tamoxifen, Toremifene and Chloroquine on the Lysosomal Enzymes in Cultured Retinal Pigment Epithelial Cells

Toimela

Salminen

Tähti

1998

Pharmacology & Toxicology

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Abstract:Retinal pigment epithelial cells carry out phagocytosis and digestion of material shed from the photoreceptor outer segments. In this process, the integrity of lysosomal enzymes is of major importance. In the present study the effects of tamoxifen, toremifene and chloroquine on the activity of two lysosomal enzymes (cathepsin D and N-acetyl-P-Dglucosaminidase) in the retinal pigment epithelial cells were studied. Retinal pigment epithelial cells from pig eyes were cultured for two weeks in Dulbecco's Modified Eagle Medium, after which the cells were exposed to 1-40 pM concentrations of tamoxifen citrate, toremifene citrate and chloroquine diphosphate. To eliminate possible medium-borne oestrogenic mechanisms, the test was repeated using phenol red-free medium with charcoal-stripped fetal calf serum. The exposure time was one week, after which the lysosomal enzymes cathepsin D and N-acetyl-P-glucosaminidase were determined. Cellular injuries were assessed by quantifying the leakage of lactate dehydrogenase into the culture medium. Cathepsin D and N-acetyl-P-D-glucosaminidase showed different sensitivities to tamoxifen, toremifene and chloroquine. The main lysosomal protease cathepsin D was more sensitive than N-acetyl-P-D-glucosaminidase to the effects of tamoxifen and toremifene, possibly due to their antioestrogenic properties. The phenol red-free medium with charcoal-stripped serum seemed to make the drugs more effective than the reference medium. Chloroquine had only a minor effect on the lysosomal protease cathepsin D, but a clearer effect could be seen on N-acetyl-P-glucosaminidase.

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Section: Discussionmentioning

confidence: 99%

Effects of Tamoxifen, Toremifene and Chloroquine on the Lysosomal Enzymes in Cultured Retinal Pigment Epithelial Cells

Toimela

Salminen

Tähti

1998

Pharmacology & Toxicology

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“…Toremifene was absorbed well from the GI tract [1]. The steady-state concentration of unchanged toremifene in the serum at 60 mg daily dose was about 600ng/ml.…”

Section: Pharmacokinetics and Metabolism Of Toremifene In Humansmentioning

confidence: 99%

Introduction to toremifene

Kangas¹

1990

Breast Cancer Res Tr

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Toremifene, a triphenylethylene antiestrogen first synthesized in 1981, binds to the estrogen receptor with an affinity about 5% that of estradiol. Its antiestrogenicity/estrogenicity ratio in animal models is about 5 times that of tamoxifen, though it requires somewhat higher doses for full effectiveness, and it is active against breast cancer in animal and cell culture models. It has a long elimination half-life and there are several metabolites, but the principal antitumor activity appears to be due to the unchanged drug. In Phase I and Phase II clinical trials, toremifene has shown good response rates in ER-positive or ER-unknown tumors, and significant responses after failure of tamoxifen or other hormonal or chemotherapeutic regimens, with rare and mild side effects.

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“…Therapeutic doses of tamoxifen and toremifene cause serum concentrations of 3.0-3.5 mM for tamoxifen (Stuart et al 1992) and 2 mM for toremifene (Anttila et al 1990). Since the tissue levels of tamoxifen can be 10-60 times higher than their serum levels (Lien et al 1991), the concentrations used in the present study are within a relevant range.…”

Section: Discussionmentioning

confidence: 86%

The Phagocytosis of Rod Outer Segments is Inhibited by Selected Drugs in Retinal Pigment Epithelial Cell Cultures

Mannerström

Mäenpää

Toimela

et al. 2001

Pharmacology & Toxicology

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The effects of tamoxifen, toremifene and chloroquine on the phagocytosis of rod outer segments by retinal pigment epithelium were evaluated in human retinal pigment epithelial cell line D407 and pig retinal pigment epithelial cell culture. Retinal pigment epithelial cells were exposed to different concentrations of tamoxifen (1-20 mM), toremifene (1-20 mM) and chloroquine (1-1000 mM), and challenged with FITC-labeled rod outer segments for 24 hr. The phagocytized (bound and ingested) rod outer segments were measured fluorometrically, and the effect of the drugs on the phagocytosis was determined. The cytotoxicity of the drugs was evaluated by measuring their effects on mitochondrial enzyme activities (WST-1-test). The results showed that the test compounds inhibited the phagocytosis of rod outer segments in both D407 and pig retinal pigment epithelial cells. The phagocytic activity was more sensitive to tamoxifen (EC 50 7.2 mM for D407 cells and 3.6 mM for pig retinal pigment epithelial cells) and toremifene (EC 50 6.2 mM and 3.1 mM respectively) than to chloroquine (EC 50 77.2 mM for D407 cells). The inhibition of rod outer segment phagocytosis in both cell cultures started at lower dose levels of test compounds than the cytotoxicity indicated by the WST-1-test. The experiments were carried out both in serum-free medium and serum-containing medium. Serum seemed to be a critical factor in the medium and caused difficulties in the interpretation of the results.The phagocytosis of rod outer segments by the retinal pigment epithelium is one of the most important functions of these cells and essential for retinal homeostasis (Young 1969). The mechanisms of phagocytosis are complex and incompletely understood. The stages involve the recognition and binding of rod outer segments to retinal pigment epithelial cells, ingestion of rod outer segments, and digestion by lysosomal enzymes. The phagocytosis of rod outer segments is a highly specific receptor-mediated process (Hall & Abrams 1984;Mayerson & Hall 1986). However, cultured retinal pigment epithelial cells of one species are able to phagocytize rod outer segments isolated from another species (Reid et al. 1992). Disturbances in the phagocytosis can result in the accumulation of rod outer segment debris in the subretinal space, which can cause retinal degeneration and eventual blindness (Bok & Hall 1971; Edwards & Szamier 1977). Several agents, such as lysosomal enzyme inhibitors (Kennedy et al. 1994), protein glycosylation inhibitors (Hall et al. 1988;Boyle & McLaughlin 1990) and compounds that increase intracellular cAMP, reduce the rod outer segment phagocytosis by retinal pigment epithelial cells (Edwards & Bakshian 1980;Hall et al. 1993;Kuriyama et al. 1995).Chloroquine has been shown to be oculotoxic. It accumulates in the retina and causes degeneration in photoreceptors and retinal pigment epithelium in vivo (Rosenthal et al. 1978). In vitro chloroquine reduces the viability of retinal Author for correspondence: Hanna Tähti, Medical School, Universi...

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Pharmacokinetics of toremifene

Cited by 55 publications

References 3 publications

Effects of Tamoxifen, Toremifene and Chloroquine on the Lysosomal Enzymes in Cultured Retinal Pigment Epithelial Cells

Effects of Tamoxifen, Toremifene and Chloroquine on the Lysosomal Enzymes in Cultured Retinal Pigment Epithelial Cells

Introduction to toremifene

The Phagocytosis of Rod Outer Segments is Inhibited by Selected Drugs in Retinal Pigment Epithelial Cell Cultures

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