Oral Administration Of Tamoxifen Research Articles

Pharmacokinetic interaction between tamoxifen and ondansetron in rats: non-competitive (hepatic) and competitive (intestinal) inhibition of tamoxifen metabolism by ondansetron via CYP2D subfamily and 3A1/2

Tamoxifen and ondansetron were commonly metabolized via rat hepatic CYP2D subfamily and 3A1/2, and ondansetron is used to treat chemotherapy-induced nausea. The purpose of this study was to report the pharmacokinetic interaction between tamoxifen and ondansetron in rats. The pharmacokinetics of tamoxifen and ondansetron were evaluated after the intravenous and oral administration of tamoxifen, ondansetron, and both drugs together to rats. The Vmax (maximum velocity), Km (apparent Michaelis-Menten constant), CLint (intrinsic clearance), Ki (inhibition constant), and [I] (concentration of inhibitor in the liver and intestine)/Ki ratio of ondansetron were also measured. The AUC0-infinitys of tamoxifen were significantly greater after both intravenous and oral administration with ondansetron compared to those of tamoxifen alone. The significantly slower hepatic and intestinal CLints for the disappearance of tamoxifen with both drugs together were due to inhibition of metabolism of tamoxifen by ondansetron via CYP2D subfamily and 3A1/2. The significantly greater AUC0-infinity of tamoxifen after the intravenous administration of both drugs together could have possibly been attributable to a non-competitive (hepatic) inhibition of CYP2D subfamily- and 3A1/2-mediated tamoxifen metabolism by ondansetron. The significantly greater AUC0-infinity of tamoxifen after the oral administration of both drugs together could have been attributable to a competitive (intestinal) inhibition of CYP2D subfamily- and 3A1/2-mediated tamoxifen metabolism by ondansetron in addition to non-competitive inhibition in the liver.

Topical tamoxifen gel (afimoxifene) is associated with low plasma levels of 4-OHT while achieving therapeutic local antiestrogenic effect in premenopausal women with cyclical mastalgia.

Abstract Abstract #2154 Background:4-hydroxytamoxifen(4-OHT) is a potent anti-estrogenic metabolite of tamoxifen with a much higher affinity for estrogen receptors than tamoxifen.We compared the plasma levels of 4-OHT in subjects applying Afimoxifene gel with subjects on oral tamoxifen.We conducted a randomized clinical trial to evaluate the safety and efficacy of topical Afimoxifene gel for the treatment of moderate-to-severe cyclical mastalgia.
 Methods:Plasma levels of 4-OHT in 19 healthy premenopausal women taking 20 mg/d oral tamoxifen for at least 2 months were compared with those of 16 healthy premenopausal women assigned to apply 4mg 4-OHT in a 0.228% Afimoxifene gel daily for 21 days in a pharmacokinetic(PK) study.Plasma for PK sampling was obtained at multiple time-points.PK parameters of plasma 4-OHT Cmax, and AUC0-24ht were determined.
 To evaluate the clinical effectiveness of the gel, premenopausal women aged at least 18 years experiencing moderate-to-severe mastalgia were randomized to receive placebo, 2mg or 4 mg of Afimoxifene daily delivered as a transdermal hydroalcoholic gel for 4 menstrual cycles.The primary efficacy parameter was change in mean pain intensity, as measured by the Visual Analog Scale(VAS) for the seven worst pain score days within a cycle, from baseline to the fourth cycle.Plasma levels of 4-OHT were assessed once after the second and the fourth menstrual cycles.
 All plasma levels of 4-OHT were measured in the same central lab, with a GC-MS method with a lower limit of quantification of 5 pg/mL.
 Results:In the PK studies, the 4-OHT plasma levels following oral tamoxifen administration were 16-18 times higher than 4-OHT levels following 4mg 4-OHT administration by topical gel. At steady state, mean Cmax levels in the Afimoxifene group and oral tamoxifen group were 149+99 pg/mL and 2398+901 pg/mL respectively. The Cave concentrations, derived from AUC0-24h/24, were 117+77 pg/mL(Afimoxifene) and 2078+811 pg/mL(oral tamoxifen).
 After 4 cycles of gel treatment, statistically significant improvements relative to placebo were measured in mean VAS score in the 4-mg Afimoxifene group(-12.71 mm[95% confidence interval, -0.96 to -24.47; P = 0.034]).Patient global assessment of pain, physician assessment of pain, tenderness on palpation and nodularity following 4 cycles of treatment were significantly improved in the 4-mg group, compared with placebo(P = 0.010 [pain]; P = 0.012 [tenderness]; P = 0.017 [nodularity]).Systemic exposure was low, with mean 4-OHT plasma levels of 50±64 pg/mL. There were no changes in menstrual pattern or plasma hormone levels and no breakthrough vaginal bleeding in patients treated with Afimoxifene.
 Conclusion:Topical application avoids high systemic exposure to 4-OHT compared with oral tamoxifen, a 16-18-fold difference, thus potentially reducing the risk of systemic side-effects.Afimoxifene is an effective treatment for moderate-to-severe mastalgia in premenopausal women and has the potential to be used for breast cancer chemoprevention/gynecomastia in the future. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2154.

Enhanced tamoxifen bioavailability after oral administration of tamoxifen in rats pretreated with naringin

The aim of this study was to investigate the effect of naringin on the bioavailability and pharmacokinetics of tamoxifen and of its metabolite, 4-hydroxytamoxifen in rats. The pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen were determined by HPLC after pretreating with naringin (1.5, 7.5, and 15 mg/kg) 30 min before orally administering tamoxifen (10 mg/kg). Compared with the control group (treated with tamoxifen alone), naringin pretreated animals showed significantly (p<0.01) increased areas under the plasma concentration-time curves (AUC) and peak tamoxifen concentrations (Cmax). The absolute bioavailabilities (AB%) of tamoxifen in naringin pretreated animals were enhanced versus control (from 32.8% to 47.1%), and the relative bioavailabilities (RB%) of tamoxifen in the naringin pretreated groups were 2.02-2.88 times higher than that in the control. No significant changes in the terminal half-life (t(1/2)) or Tmax of tamoxifen were observed in the naringin pretreated groups. The AUCs of 4-hydroxytamoxifen after pretreating naringin were also significantly elevated (p<0.05) versus the control. But metabolite ratios (MR; AUC of 4-hydroxytamoxifen to tamoxifen) were significantly lower. These results suggest that the enhanced bioavailability of tamoxifen in the presence of naringin might be due to the inhibition of CYP3A4 by naringin. If the results of this study are further confirmed by clinical trials, tamoxifen dosages should be adjusted to avoid potential drug interaction when tamoxifen is used clinically in combination with naringin-containing dietary supplements.

Effects of Oral Administration of Tamoxifen, Toremifene, Dehydroepiandrosterone, and Vorozole on Uterine Histomorphology in the Rat

Effects of Oral Administration of Tamoxifen, Toremifene, Dehydroepiandrosterone, and Vorozole on Uterine Histomorphology in the Rat

Influence of gender on tamoxifen-induced biochemical changes in serum of rats

Tamoxifen, the widely prescribed drug in the prevention and therapy of breast cancer, may cause side effects which may be influenced by gender. The present study was undertaken to investigate the impact of gender on tamoxifen-induced toxic and biochemical changes following oral administration of tamoxifen at high dose level of 20 mg/kg once daily for a 2-week period in both male and female rats. The results showed marked increases in serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in female rats. In contrast, treatment with tamoxifen in male animals significantly decreased the activity of ALT, with a tendency for a decrease in serum AST levels. In female rats, a significant reduction in the serum activity of acid phosphatase (ACP) was noted, compared with a non-significant decrease in males. Non-significant changes in serum levels of alkaline phosphatase (ALP) were seen in both sexes. Tamoxifen lowered serum contents of total lipid and total cholesterol in both male and female rats. Serum levels of triglycerides were reduced in female rats as compared to a non-significant decrease in male animals. The serum albumin concentration was decreased in both male and female rats, while total protein was decreased only in female animals. Tamoxifen markedly increased serum levels of creatinine in female rats, compared with a non-significant rise in males. Total serum contents of calcium were similarly reduced in both males and females. This is the first study which points to gender-related differences in tamoxifen-induced toxic and metabolic changes in rats. The results indicated that females are more susceptible than males to tamoxifen toxicity, probably due to the ability of tamoxifen to antagonize the action of estrogen in females.

Optimization of spatiotemporal gene inactivation in mouse heart by oral application of tamoxifen citrate

Inducible and tissue-specific gene inactivation in mice has become a powerful tool to bypass embryonic and postnatal lethality of knockout mice. The most frequently used inducible system is based on Cre recombinase fused to either one or two mutated estrogen receptor ligand binding domains, thus rendering Cre function tamoxifen-dependent. To achieve Cre-mediated inactivation of a given gene, 4-OH tamoxifen (4-OHT) dissolved either in alcohol and/or oil is usually administered by repeated intraperitoneal (i.p.) injections. Since this procedure imposes considerable stress on mice, we compared the effect of tamoxifen citrate, mixed into a standard mouse diet at different concentrations, with that of i.p. administration of 4-OHT on Cre-mediated, heart-specific inactivation of thioredoxin reductase 2. Here we show that tamoxifen citrate in the chow was equally effective as 4-OHT given i.p. Oral tamoxifen administration is thus a convenient and cost-saving way for gene induction, and, most importantly, it reduces stress and avoids adverse effects in mice.

Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats

Orally administered tamoxifen undergoes a first-pass metabolism and substrates for multidrug resistance (MDR) transporters efflux in the liver and intestines, which obstructs its systemic exposure. This study investigated the effect of quercetin, a dual inhibitor of CYP3A4 and P-gp, on the bioavailability and pharmacokinetics of tamoxifen and one of its metabolites, 4-hydroxytamoxifen, in rats. The pharmacokinetic parameters of tamoxifen and 4-hydroxytamoxifen in plasma were determined after orally administering tamoxifen (10 mg/kg) with or without quercetin (2.5, 7.5 and 15 mg/kg). The coadministration of quercetin (2.5 and 7.5 mg/kg) significantly ( p < 0.05) increased the absorption rate constant ( K a), peak concentration ( C max) and the areas under the plasma concentration-time curve (AUC) of tamoxifen. The absolute bioavailability (AB%) of tamoxifen with 2.5 and 7.5 mg/kg quercetin ranged from 18.0% to 24.1%, which was significantly higher than the control group, 15.0% ( p < 0.05). The relative bioavailability (RB%) of tamoxifen coadministered with quercetin was 1.20–1.61 times higher than the control group. The coadministration of quercetin caused no significant changes in the terminal half-life ( t 1/2) and the time to reach the peak concentration ( T max) of tamoxifen. Compared with the control group, the coadministration of 7.5 mg/kg quercetin significantly ( p < 0.05) increased the AUC of 4-hydroxytamoxifen. However, the metabolite ratios (MR; AUC of 4-hydroxytamoxifen to tamoxifen) were significantly lower ( p < 0.05). This suggests that quercetin inhibits the both MDR transporters efflux and first-pass metabolism of tamoxifen. The enhanced bioavailability of tamoxifen as a result of its coadministration with quercetin might be due to the effect of quercetin promoting the intestinal absorption and reducing the first-pass metabolism of tamoxifen. If the results are further confirmed in the clinical trials, the tamoxifen dosage should be adjusted when tamoxifen is administered with quercetin or quercetin-containing dietary supplements in order to avoid potential drug interactions.

Combined efficacy of tamoxifen and coenzyme Q10 on the status of lipid peroxidation and antioxidants in DMBA induced breast cancer

An increasing amount of experimental and epidemiological evidence implicates the involvement of oxygen derived radicals in the pathogenesis of cancer development. It is well known that chemical carcinogenesis is multistage process. Free radicals arefound to be involved in both initiation and promotion of multistage carcinogenesis. Tamoxifen (TAM) is a potent antioxidant and a non-steroidal antiestrogen drug most used in the chemotherapy and chemoprevention of breast cancer. Besides its anticarcinogenic potential, it also produces some adverse toxic side effects, while taken for a long time. In order to minimise the side effects and to improve the antioxidant efficacy of tamoxifen, coenzyme Q10 (CoQ10) was added. Hence the present study was designed to investigate the combined efficacy of TAM along with CoQ10 in 7, 12 dimethyl benz(a)anthracene (DMBA) induced peroxidative damage in rat mammary carcinoma. The experimental setup comprised of one control and five experimental groups and it was carried out in adult female Sprague-Dawley rats. Mammary carcinoma was induced by oral administration of DMBA (25 mg kg(-1) body wt) and the treatment was started by the oral administration of TAM (10 mg kg(-1) body wt day(-1)) and CoQ10 (40 mg kg(-1) body wt day(-1)) dissolved in olive oil and continued for 28 days. Rats induced with DMBA showed a decline in the thiol capacity of the cell accompanied by high malondialdehyde content levels along with lowered activities of antioxidant status (superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione). In contrast, glutathione metabolising enzymes (glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) were increased significantly in chemically induced carcinoma bearing rats. Administration of TAM along with CoQ10 restored the activities to a significant level thereby preventing cancer cell proliferation. This study highlights the increased antioxidant enzyme activities in relation to the susceptibility of cells to carcinogenic agents and the response of tumour cells to the chemotherapeutic agents.

CYP17 polymorphism as a risk factor of tamoxifen-induced hepatic steatosis in breast cancer patients

Oral administration of tamoxifen, an endocrine therapy for breast cancer, often induces hepatic steatosis (THS, tamoxifen-induced hepatic steatosis) as a complication, which can progress to non-alcoholic steatohepatitis (NASH). The development of this complication is strongly associated with three clinical risk factors; specifically, insulin resistance, central obesity, and hypertriglyceridemia, however a genetic predisposition to THS has yet to be investigated. The aim of this study is to determine whether genetic polymorphism of the P450c17alpha enzyme coded for by the CYP17 gene, responsible for regulating serum estrogen, has an association with THS. After obtaining informed consent from 180 eligible breast cancer patients treated with tamoxifen, DNA was collected and analyzed by restriction fragment length polymorphism assay and classified into alleles defined as A1 and A2. The absence or presence and extent of THS was evaluated by calculating the liver/spleen (L/S) ratio based on Hounsfield units with a CT scanner. Administration of tamoxifen led to THS (L/S ratio <0.9) in 57 (31.7%) of 180 patients while the remaining 123 (68.3%) patients did not develop THS. A significant difference in the distribution of CYP17 genotypes was observed between patients who developed THS and those who did not (P=0.021). A significantly higher frequency of the A2 allele was seen in the THS group (odds ratio, 1.90; 95% confidence interval, 1.21-2.99). Our study provides the first evidence that CYP17 polymorphism participates in the development of THS, and sheds light on the genetic causes of this side effect and genetic differences between tamoxifen-treated individuals.

Augmented efficacy of tamoxifen in rat breast tumorigenesis when gavaged along with riboflavin, niacin, and CoQ 10: Effects on lipid peroxidation and antioxidants in mitochondria

Reactive oxygen species (ROS) play a major role in causing mitochondrial changes linked to cancer and metastasis. Uptake of antioxidants by tissue to reduce the ROS production could be instrumental in controlling cancer. Tamoxifen (TAM), a nonsteroidal anti-estrogen drug most used in the chemotherapy and chemoprevention of breast cancer. Riboflavin, niacin and coenzyme Q 10 (CoQ 10) are proved to be potent antioxidants and protective agents against many diseases including cancer. The objective of this research is to determine the therapeutic efficacy of combinatorial therapy on mammary carcinoma bearing rats in terms of the mitochondrial lipid peroxidation and antioxidant status especially MnSOD. Female albino rats of Sprague–Dawley strain were selected for the investigation. Mammary carcinoma was induced with 7,12-dimethyl benz(a)anthracene (DMBA: 25 mg), and the treatment was started by the oral administration of TAM (10 mg/kg body weight/day) along with riboflavin (45 mg/kg body weight/day), niacin (100 mg/kg body weight/day) and CoQ 10 (40 mg/kg body weight/day) for 28 days. The levels of lipid peroxides, activities of enzymic and non-enzymic antioxidants were measured in the mitochondria isolated from the mammary gland and liver of control and experimental rats. Rats treated with DMBA showed an increase in mitochondrial lipid peroxidation (mammary gland 52.3%; liver 25.1%) accompanied by high malondialdehyde levels along with lowered activities of mitochondrial enzymic antioxidants [superoxide dismutase (mammary gland 19.9%; liver 24.8%), catalase (mammary gland 50%; liver 19.7%), glutathione peroxidase (mammary gland 47.8%; liver 31.1%)] and non-enzymic antioxidants [reduced glutathione (mammary gland 14.3%; liver 13.3%), Vitamin C (mammary gland 6.49%; liver 21.4%) and E (mammary gland 20.3%; liver 22.2%)]. Administration of combinatorial therapy restored lipid peroxide level and the activities of enzymic and non-enzymic antioxidants to near normalcy. In addition, antitumour activity was also found to be enhanced which is evident from the increased expression of tumour suppressor gene MnSOD thereby preventing cancer cell proliferation. These results suggested that TAM treatment is the most effective during co-administration of riboflavin, niacin and CoQ 10 in terms of mitochondrial antioxidant and antitumour activity.

Tamoxifen inhibits endothelial cell proliferation and attenuates VEGF-mediated angiogenesis and migration in vivo

Introduction: Angiogenesis is fundamental to tumour growth and vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic cytokines known. We have previously demonstrated that tamoxifen reduces serum VEGF in certain cancer patients. We hypothesized that tamoxifen may attenuate the angiogenetic response to VEGF. Methods: Human dermal microvessel endothelial primary cell cultures (HMEC) were incubated with tamoxifen (1.25–5.0 μg) or vehicle. Cell proliferation was quantified using 5-bromo-2′-deoxyuridine (BrdU) labelling endothelial cell proliferation assay. The effect of oral tamoxifen (20 mg/day) on VEGF-mediated angiogenesis in vivo was assessed using a Matrigel angiogenesis assay in the Sprague–Dawley rat. Results: Tamoxifen (5.0 μg/ml) significantly reduced HMEC proliferation over 24 h when compared with cells treated with vehicle alone. Oral administration of tamoxifen in the rat (20 mg/day) significantly reduced endothelial cell proliferation and migration in response to VEGF. Conclusion: Tamoxifen (5.0 μg/ml) reduces proliferation of a VEGF-dependent endothelial cell line in vitro. In vivo, orally administered tamoxifen reduces VEGF-mediated angiogenesis in the rat. These findings indicate that tamoxifen may directly inhibit the effect of VEGF on the endothelial cell, in addition to its previously described effect of reducing serum VEGF levels. This data supports a role for tamoxifen in modulation of the VEGF-dependent angiogenic response to surgical trauma, particularly as an adjuvant therapy for VEGF-dependent tumours.

Effect of paternal administration of an antiestrogen, tamoxifen on embryo development in rats

We have earlier reported that oral administration of tamoxifen causes a dose-dependent reduction in the fertility of adult male rats. The decrease in fertility was mainly due to an increase in pre-implantation loss without an effect on fertilizing ability. During the study, an increased incidence of post-implantation loss of conceptuses sired by tamoxifen-treated male rats was observed. A detailed study was undertaken to investigate dose-related changes in pre- and post-implantation loss and the stage(s) of development at which these losses occurred. The present study demonstrates that tamoxifen treatment produced few normal litters as well as significantly increased pre-implantation loss without affecting the rate of fertilization. Also a significant increase in the number of degenerating embryos at the 2–4-cell stage (days 1–2 of gestation), retrieved from the oviduct/uterus of females mated with tamoxifen-treated males was observed. Histology of the resorbed fetuses, in both control and treated groups, showed presence of trophoblast outgrowth indicative of early placenta formation, which normally occurs on days 8–9 of gestation. The present results suggest that pre-implantation loss occurred at the 2–4-cell stage and the post-implantation loss occurred around days 8–9 of gestation, i.e. around midgestation. The possible effects of paternal tamoxifen treatment on embryogenesis may be due to the reduction of androgens or by the blockage of the estrogen receptor by tamoxifen, thereby affecting germ cell maturation during spermatogenesis.

Phase I and pharmacokinetic analysis of high-dose tamoxifen and chemotherapy in normal and tumor-bearing dogs.

To determine whether tamoxifen plasma concentrations capable of blocking P-glycoprotein (Pgp) in vitro can be safely achieved in dogs and whether doxorubicin pharmacokinetic alterations occur when tamoxifen is coadministered. Tamoxifen dose escalation studies were conducted in 7 normal dogs and in 19 tumor-bearing dogs receiving full-dose chemotherapy. Plasma tamoxifen and serum doxorubicin disposition were analyzed for putative drug interactions. Steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen (NDMT) were 5-10 microM following oral tamoxifen administration at 600 mg/m2 every 12 h for 7 days to normal and tumor-bearing dogs. Mild-moderate gastrointestinal toxicity (diarrhea, anorexia) and reversible neurotoxicity were observed in dogs receiving chemotherapy plus high-dose tamoxifen. Myelosuppression was not affected by combined treatment in tumor-bearing dogs. High-dose tamoxifen decreased the clearance and volume of distribution of full-dose doxorubicin. Concentrations of tamoxifen/ NDMT sufficient to inhibit Pgp may be achieved in dogs receiving full-dose chemotherapy with a moderate but acceptable increase in gastrointestinal toxicity. Tamoxifen affects doxorubicin metabolism in dogs at high doses resulting in increased serum exposure. Pharmacologic manipulation of Pgp expression or function in normal and tumor tissue in dogs may facilitate investigation of novel anticancer treatment strategies in humans.

Opioidergic regulation of prolactin secretion during pregnancy: role of ovarian hormones.

We have recently demonstrated the existence of a neuromodulatory regulation of prolactin secretion by the opioid system showing a paradoxical opioid-induced prolactin suppression at the end of pregnancy. The aim of this study was to determine a possible interaction between the opioid system and ovarian hormones on the release of prolactin during pregnancy. Serum prolactin levels measured at 1800 h were significantly higher on days 3 and 6 of pregnancy when compared with the other days of gestation. These increases in serum prolactin were reduced significantly by naloxone (2 mg/kg) administered at 1730 h and by RU-486 (10 mg/kg) administered at 0800 h. The response induced by RU-486 was potentiated by naloxone only on day 3. On days 7, 13 and 16, prolactin secretion was not modified by RU-486 and/or naloxone treatment. In RU-486 pretreated rats, naloxone administration increased serum prolactin levels only on day 16 of pregnancy. Interestingly, progesterone treatment (0.5 mg/rat) on days 13, 14 and 15 of pregnancy prevented the high increase in serum prolactin induced by RU-486 and naloxone on day 16 of pregnancy. The progressive increase and decrease of serum progesterone concentration during pregnancy was not modified by naloxone treatment. The participation of oestrogen in the regulation of prolactin secretion by the opioid system on days 3, 16 and 19 was examined by treating these groups of rats with oestradiol benzoate or tamoxifen citrate. Oestradiol (2 micrograms/rat) significantly increased serum prolactin levels on day 3 and naloxone administration did not modify this increase. No effect was observed after oestradiol (5 micrograms/rat) and naloxone treatment on days 16 and 19 of pregnancy. Oral administration of tamoxifen (500 micrograms/kg) the previous day did not modify the serum prolactin concentration measured at 1800 h in oil-treated rats on days 3, 16 and 19 of pregnancy. The antioestrogen completely abolished the naloxone-induced prolactin secretion on day 16 in rats pretreated with RU-486 but no effect was observed on day 19. When tamoxifen was administered on days 14 and 15 of pregnancy, the high serum prolactin levels on day 19 induced by treatment with RU-486 and naloxone were significantly reduced. In conclusion, these results provide an important new insight into the existence of a dual neuromodulatory regulation of prolactin secretion by the opioid system during pregnancy. After a stimulatory action during the first days, there is a change to an inhibitory control at the end of pregnancy, starting around day 16. Moreover, the activation of the inhibitory modulation of the opioid system on prolactin secretion on days 16 and 19 of pregnancy seems to be mediated by changes in the oestrogen and progesterone action.

Effect of tamoxifen on the pharmacokinetics of theophylline in rats.

The effect of tamoxifen on the pharmacokinetics of theophylline was investigated in male Sprague-Dawley rats. The oral administration of tamoxifen at a dose equal to 40 mg kg-1 48 h before the intravenous injection of theophylline 10 mg kg-1, significantly (P < 0.05) increased the clearance of theophylline by 39%, with no apparent effect on the volume of distribution. As a consequence, the elimination half-life of theophylline was significantly (P < 0.05) shortened in the tamoxifen-treated rats (3.56 +/- 0.39 h vs 5.25 +/- 0.48 h) as well as its mean residence time (5.04 +/- 0.60 h vs 7.50 +/- 0.75 h). Although these data cannot be directly extrapolated to the clinical situation, they provide experimental support to suggest that more attention should be paid to the potential risk of pharmacokinetic interactions in the presence of tamoxifen.

Tamoxifen: evidence by 32P-postlabeling and use of metabolic inhibitors for two distinct pathways leading to mouse hepatic DNA adduct formation and identification of 4-hydroxytamoxifen as a proximate metabolite.

Exposure to pentachlorophenol (PCP) strongly intensifies the formation of mouse hepatic DNA adducts elicited by oral administration of tamoxifen (TAM), as previously shown by 32P-postlabeling. To explain this effect, PCP was proposed to interfere with the detoxication by sulfate conjugation of an as yet unidentified hydroxylated proximate TAM metabolite. A comparison of the present and earlier results shows that the hepatic TAM adduct pattern in female ICR mice depended on the route of administration of TAM (120 mumol/kg), with oral administration primarily eliciting formation of more polar adducts (termed group I adducts), while after i.p. administration less polar adducts (group II) predominated over group I adducts by a factor of 17.5. All these adducts were also formed in female Sprague-Dawley rats after i.p. dosing with TAM, but total adduct levels were 3.5- to 5-fold higher than in mice. After four daily i.p. treatments, TAM adducts accumulated in mouse liver DNA in a non-linear fashion. Adduct levels were 30-50 times lower in mouse kidney and lung than in liver. The phenolic metabolite 4-hydroxy TAM (120 mumol/kg) exclusively led to formation of polar (group I) hepatic adducts, and this process was stimulated 8-fold by co-administration of PCP (75 mumol/kg). Co-administration of PCP with the parent compound led to an 11-fold enhancement of group I adduct formation; simultaneously, levels of group II adducts were suppressed 6-fold. Another inhibitor of sulfate conjugation, 2,6-dichloro-4-nitrophenol, unlike PCP, had no effect on group I adducts, but it reduced group II adduct formation 2.2-fold. The PCP metabolite 2,3,5,6-tetrachlorohydroquinone (75 mumol/kg) did not significantly affect any major TAM adduct, suggesting that PCP itself was the active compound. Similar to group II TAM adducts, the formation of hepatic safrole-DNA adducts was inhibited in female ICR mice by both sulfotransferase inhibitors, consistent with the proposal that metabolic alpha-hydroxylation of the ethyl group of TAM followed by sulfate conjugation represented a mechanism of TAM activation. On the other hand, the strong intensification of group I adducts by PCP and the lack of this effect by 2,6-dichloro-4-nitrophenol suggested that inhibition of sulfate conjugation may not have been the primary mechanism underlying the intensification of group I adducts formed from TAM or 4-hydroxy TAM. The results presented herein demonstrate conclusively that TAM was activated to DNA-reactive compounds along two distinct pathways which contrasted in their responses to metabolic inhibitors.

The effect of LHRH-a on HCG and progesterone secretion by human placenta in vitro

In this study the effects of luteinizing hormone-releasing hormone (LHRH)-A on the human chorionic gonadotropin (HCG) and progesterone secretion of human placental tissues of different gestational ages; placental tissues from women receiving oral administration of tamoxifen; and placental tissue from early pregnant women in the presence of tamoxifen were observed. The results are as follows: 1) In the placental tissues from early gestation of 10-12 weeks LHRH-A could stimulate HCG secretion but had an obvious inhibitory effect on progesterone secretion. Since the placenta has been demonstrated to contain endogenous LHRH-like peptide it is suggested that the endogenous LHRH-like peptide might exert a regulatory effect on placental HCG and progesterone secretion at different gestational ages. 2) In the present study the placental villous cells from the early pregnant women of 6-7 week gestation with or without oral administration of tamoxifen were cultured in vitro. The results showed that the response of placental villous cells from the tamoxifen treated women to LHRH-A was lower than those from untreated women. 3) The placental villous tissues from the pregnant woman of 6-7 week gestation were cultured in vitro in the presence of absence of tamoxifen. The results showed that the response of placental villous tissues to LHRH-A in the presence of tamoxifen was lower than that in the absence of tamoxifen. From the results it was clear that the effects of LHRH-A on the placental villous tissues treated by exogenous addition or oral administration of tamoxifen were lower than that on untreated villous tissues. It is therefore suggested that the endogenous LHRH-like peptide might take part in the inhibitory effect of tamoxifen on the secretion of placental villous tissues which might be the reason why tamoxifen could potentiate the early pregnancy terminating effect of 15-methyl-prostaglandin F2alpha. (full text)

Effective sequential administration of tamoxifen and medroxyprogesterone acetate for 7,12-dimethylbenz[a-anthracene-induced rat mammary tumors in relation to hormone receptors.

The effects of two hormonal agents with different mechanisms of action, medroxyprogesterone acetate (MPA) and tamoxifen (TAM), on the tumor growth and hormone receptor status were evaluated in rat mammary tumors induced by 7,12-dimethylbenz[alpha]anthracene (DMBA). All estrogen receptor-positive (ER(+)) tumors became ER-negative (ER(-)), and 3 out of 4 progesterone receptor-negative (PgR(-)) and ER(+) tumors became PgR-positive (PgR(+)) after daily, oral administration of TAM for 2 weeks. In contrast, ER and PgR remained unchanged after daily administration of MPA for 2 to 4 weeks. All the ER(+) and PgR(-) tumors were transformed into PgR(+) after daily treatment with MPA for 2 weeks and then with TAM for another 2 weeks, but tumor regression was modest and none disappeared completely. In contrast, complete remission was achieved in all ER(+) tumors in the group treated with TAM for 2 weeks and then with MPA for another 2 weeks. The results suggest that the antitumor activity of the latter treatment regimen was significantly higher than that of the former. The possible mechanisms of antitumor activity of two hormonal agents are discussed.

Effect of the anti-oestrogen tamoxifen on plasma levels of luteinizing hormone, follicle-stimulating hormone, prolactin, oestradiol and progesterone in normal pre-menopausal women.

Plasma levels of LH, FSH, prolactin, oestradiol and progesterone were determined daily during two consecutive menstrual cycles in six women volunteers. During the first (control) cycle no treatment was given and normal secretion of these hormones was observed. Oral administration of tamoxifen (20 mg/day), for either 5 or 10 days of the follicular phase of the second cycle, caused no change in either the overall length of the cycle or the time of occurrence of the mid-cycle gonadotrophin surge. There was little difference in the secretion of LH, FSH and progesterone during the control and test cycles. A two- to eight-fold increase in oestradiol levels was observed during test cycle which was most pronounced at the times of mid-cycle and mid-luteal hormone peaks. There was a significant decrease in plasma prolactin levels at mid-cycle but no real difference could be seen during the remainder of the cycle. The data suggest that tamoxifen may act directly on the ovary to stimulate oestradiol release without intermediary gonadotrophin stimulation. As the drug apparently inhibited prolactin secretion even in the presence of high oestradiol levels, an alternative explanation may be that the reduced prolactin concentration permits augmented ovarian stimulation by normal concentrations of gonadotrophins.