Disposition and metabolism of a new benzothiophene antiestrogen in rats, dogs and monkeys

Lindstrom, Terry D.; Whitaker, N G; Whitaker, G. W.

doi:10.3109/00498258409151482

Cited by 43 publications

(27 citation statements)

References 4 publications

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“…However, raloxifene has poor bioavailability (Lindstrom et al, 1984). We hypothesized that extensive intestinal metabolism and enteric and enterohepatic recycling of raloxifene conjugates could explain why this drug has poor oral bioavailability but a long half-life (Fig.…”

Section: Discussionmentioning

confidence: 99%

Disposition Mechanisms of Raloxifene in the Human Intestinal Caco-2 Model

Jeong

Lin²,

Hu³

2004

J Pharmacol Exp Ther

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The purpose of this study was to determine the mechanisms responsible for transport of raloxifene and its hydrophilic conjugates. Human intestinal Caco-2 cell culture model and Caco-2 cell lysate were used for the studies. The results indicated that absorptive permeability (P AB ) of raloxifene was lower than its secretory permeability (P BA ). As the concentration increased, the efflux ratio (P BA /P AB ) decreased, but P AB increased. P AB was also increased in the presence of verapamil and cyclosporine A, two P-glycoprotein inhibitors. Raloxifene was extensively metabolized into sulfated and glucuronidated conjugates. The extent of metabolism or clearance was decreased as the concentration increased from 3.4 (96%) to 30 (22%) M. Multidrug resistance-related protein inhibitors MK-571 (C 26 H 26 ClN 2 O 3 S 2 ) and leukotriene C 4 significantly decreased (maximal 80%) apical efflux of both conjugates. They also significantly decreased (maximal 85%) basolateral efflux of glucuronides but not sulfates. On the other hand, organic anion transporter (OAT) inhibitor estrone sulfate and estrone glucuronide significantly decreased (maximal 50%) the efflux of sulfate from both sides but had variable effects on glucuronide efflux. Inhibition of conjugate efflux with the OAT inhibitor estrone sulfate was concentration dependent, which resulted in increased transport of intact raloxifene (maximal 90%). This increase in raloxifene transport was also observed in the presence of another OAT inhibitor estrone glucuronide (70%). In conclusion, this is the first report that inhibition of an efflux transporter responsible for the transport of metabolites can result in increase in the transport of the intact compound. It also provides additional explanation why raloxifene has low bioavailability but a long half-life.Raloxifene, a selective estrogen receptor modulator (Colacurci et al., 2003;Duschek et al., 2003), is used for the treatment of osteoporosis. Raloxifene blocks the adverse effects of estrogen in breast tissues and uterine endometrium while mimicking the beneficial estrogen effects on bone and lipid metabolism (MacGregor and Jordan, 1998;Scott et al., 1999). Data from both animal and human studies demonstrated that raloxifene has minimal effects on the uterus and caused no significant changes in the histological appearance of the endometrium (Scott et al., 1999 and references therein). Raloxifene is being considered as a chemopreventive agent for breast cancer (Delmas et al., 1997). Short-term clinical trials showed that raloxifene did not increase the risk of breast cancer and long-term multicenter trials are currently ongoing (Jordan and Morrow, 1999;Scott et al., 1999).Raloxifene is reported by its manufacturer to be rapidly absorbed after oral administration, but its absolute bioavailability is only 2%. This poor bioavailability is thought to be the result of extensive phase II metabolism, since it is absorbed rapidly and approximately 60% of dose was absorbed after oral dosing (Hochner-Celnikier, 1999). Acc...

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Section: Discussionmentioning

confidence: 99%

Disposition Mechanisms of Raloxifene in the Human Intestinal Caco-2 Model

Jeong

Lin²,

Hu³

2004

J Pharmacol Exp Ther

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“…In contrast to its poor bioavailability in humans, raloxifene has fairly good bioavailability in rats (39%) (Lindstrom et al, 1984). This is somewhat unexpected since the major metabolic pathway in rats is also glucuronidation.…”

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confidence: 99%

Species- And Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of Ugt1a10

Jeong¹,

Liu²,

Lin³

et al. 2005

Drug Metab Dispos

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ABSTRACT:Caco-2 cell lysate, and intestinal and liver microsomes derived from female humans and rats were used to compare and contrast the metabolism and disposition of raloxifene. In Caco-2 cell lysate, raloxifene 6-␤-glucuronide (M1) was the main metabolite, although raloxifene 4-␤-glucuronide (M2) was formed in comparable abundance (58% versus 42%). In rat liver and intestinal microsomes, M1 represented about 76 to 86% of glucuronidated metabolites. In contrast, raloxifene 4-␤-glucuronide (M2) was the predominant metabolite in expressed UGT1A10 (96%) and human intestinal (92%) microsomes. Intrinsic clearance for M2 (CL int, M2 ) in human intestinal microsomes was 33-to 72-fold higher than in rat microsomes, whereas intrinsic clearance for M1 (CL int, M1 ) was 3-to 4-fold lower. Taken together, total intrinsic clearance (CL int, M1 ؉ CL int, M2 ) in human intestinal microsomes was 3-to 6-fold higher than that in rat intestinal microsomes, but was similar in liver microsomes. In addition, intrinsic clearance in small intestinal microsomes was 2-to ϳ5-fold higher than that in hepatic microsomes, regardless of species. To account for the difference in species-and disposition model-dependent intestinal metabolism, we probed the presence of various UGT1A isoforms in Caco-2 cells using real-time reverse transcriptase-polymerase chain reaction and, as expected, detected no UGT1A10. In conclusion, the lack of UGT1A10 may explain why Caco-2 cell and rat intestinal microsomes metabolized raloxifene differently from human intestinal microsomes. The presence of human intestinal UGT1A10 and the higher overall intrinsic clearance value in the human intestine as the result of UGT1A10 expression could explain why raloxifene has much lower bioavailability in humans (2%) than in rats (39%).

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“…UGT1A8 and UGT1A10, isozymes that are absent in the human liver, are thought to glucuronidate raloxifene mainly in the intestine and lead to extremely low F (Kemp et al, 2002;Jeong et al, 2005). F of raloxifene in rats and dogs was originally reported as 39 and 17%, respec-tively (Lindstrom et al, 1984), and have been recently reported as 4 and 0%, respectively (Deguchi et al, 2011). The UGT isozymes responsible for the glucuronidation of raloxifene and its intestinal and hepatic availabilities (Fg and Fh, respectively) in preclinical animals have not been investigated adequately.…”

Section: Introductionmentioning

confidence: 99%

“…Raloxifene (1 mg/kg b.wt.) was dissolved in a solution containing ethanol, polyethylene glycol 300, and water (1:4:5) as reported previously (Lindstrom et al, 1984) and administered intravenously at a volume of 0.5 ml/kg to fasted SD rats, Wistar rats, EHBRs, and Gunn rats (n ϭ 3). Blood samples were collected from the animals at 0.05, 0.25, 0.5, 1, 2, 4, 8, and 24 h after dosing.…”

Section: Introductionmentioning

confidence: 99%

Impact of Intestinal Glucuronidation on the Pharmacokinetics of Raloxifene

Kosaka¹,

Sakai²,

Endo³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Raloxifene is extensively glucuronidated in humans, effectively reducing its oral bioavailability (2%). It was also reported to be glucuronidated in preclinical animals, but its effects on the oral bioavailability have not been fully elucidated. In the present study, raloxifene and its glucuronides in the portal and systemic blood were monitored in Gunn rats deficient in UDP-glucuronosyltransferase (UGT) 1A, Eisai hyperbilirubinemic rats (EHBRs), which hereditarily lack multidrug resistance-associated protein (MRP) 2, and wild-type rats after oral administration. The in vitro-in vivo correlation (IVIVC) of four UGT substrates (raloxifene, biochanin A, gemfibrozil, and mycophenolic acid) in rats was also evaluated. In Gunn rats, the product of fraction absorbed and intestinal availability and hepatic availability of raloxifene were 0.63 and 0.43, respectively; these values were twice those observed in wild-type Wistar rats, indicating that raloxifene was glucuronidated in both the liver and intestine. The ratio of glucuronides to unchanged drug in systemic blood was substantially higher in EHBRs (129-fold) than in the wild-type Sprague-Dawley rats (10-fold), suggesting the excretion of raloxifene glucuronides caused by MRP2. The IVIVC of the other UGT substrates in rats displayed a good relationship, but the oral clearance values of raloxifene and biochanin A, which were extensively glucuronidated by rat intestinal microsomes, were higher than the predicted clearances using rat liver microsomes, suggesting that intestinal metabolism may be a great contributor to the first-pass effect. Therefore, evaluation of intestinal and hepatic glucuronidation for new chemical entities is important to improve their pharmacokinetic profiles.

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Disposition and metabolism of a new benzothiophene antiestrogen in rats, dogs and monkeys

Cited by 43 publications

References 4 publications

Disposition Mechanisms of Raloxifene in the Human Intestinal Caco-2 Model

Disposition Mechanisms of Raloxifene in the Human Intestinal Caco-2 Model

Species- And Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of Ugt1a10

Impact of Intestinal Glucuronidation on the Pharmacokinetics of Raloxifene

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