Disposition of Lasofoxifene, a Next-Generation Selective Estrogen Receptor Modulator, in Healthy Male Subjects

Prakash, Chandra; Johnson, Kim A.; Gardner, Mark

doi:10.1124/dmd.108.020404

Cited by 17 publications

(18 citation statements)

References 33 publications

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“…Prakash, et al reported previously that neither catechol nor glutathione conjugates of LAS were detected in humans or preclinical species, and concluded that this was likely due to rapid conjugative metabolism (O-methylation, glucuronidation, or sulfation) followed by urinary excretion. 31 However, results of the present study suggest that LAS- o -quinone formation and subsequent thiol conjugation could represent a possible competing pathway, as GSH conjugates were observed alongside glucuronidated or O-methylated metabolites in incubations containing GSH in the presence of glucuronidating or methylating systems (Figure 4). Although LAS GSH conjugates have not been previously detected in vivo , our data clearly demonstrate that LAS catechols may further oxidize to thiophilic o -quinones.…”

Section: Discussionmentioning

confidence: 59%

“…30 The structural resemblance to E 2 led us to hypothesize that LAS would form similar quinoid metabolites (Scheme 1). It has been previously reported that 5-hydroxylasofoxifene (5-OHLAS) and 7-hydroxylasofoxifene (75OHLAS) catechols are formed as primary oxidative metabolites of LAS; 31 however, the potential for further oxidation of these catechols to electrophilic quinoids has not been investigated. In the current study, we have found that LAS can be oxidized both chemically and enzymatically to o -quinones which form conjugates with GSH.…”

Section: Introductionmentioning

confidence: 99%

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Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol

Michalsen

Gherezghiher

Choi

et al. 2012

Chem. Res. Toxicol.

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The bioactivation of both endogenous and equine estrogens to electrophilic quinoid metabolites has been postulated as a contributing factor in carcinogenic initiation and/or promotion in hormone sensitive tissues. Bearing structural resemblance to estrogens, extensive studies have shown that many selective estrogen receptor modulators (SERMs) are subject to similar bioactivation pathways. Lasofoxifene (LAS), a third generation SERM which has completed Phase III clinical trials for the prevention and treatment of osteoporosis, is currently approved in the European Union for this indication. Previously, Prakash et al. (Drug Metab. Dispos. 2008, 36, 1218-26) reported that similar to estradiol, two catechol regioisomers of LAS are formed as primary oxidative metabolites, accounting for roughly half of total LAS metabolism. However, the potential for further oxidation of these catechols to electrophilic o-quinones has not been reported. In the present study, LAS was synthesized and its oxidative metabolism investigated in vitro under various conditions. Incubation of LAS with tyrosinase, human liver microsomes, or rat liver microsomes in the presence of GSH as a trapping reagent resulted in formation of two mono-GSH and two di-GSH catechol conjugates which were characterized by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Similar conjugates were also detected in incubations with P450 3A4, P450 2D6, and P450 1B1 supersomes. Interestingly, these conjugates were also detected as major metabolites when compared to competing detoxification pathways such as glucuronidation and methylation. The 7-hydroxylasofoxifene (7-OHLAS) catechol regioisomer was also synthesized and oxidized either chemically or enzymatically to an o-quinone that was shown to form depurinating adducts with DNA. Collectively, these data show that analogous to estrogens, LAS is oxidized to catechols and o-quinones which could potentially contribute to in vivo toxicity for this SERM.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol

Michalsen

Gherezghiher

Choi

et al. 2012

Chem. Res. Toxicol.

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“…Based on the structures of the metabolites, six metabolic pathways of LAS were identified: hydroxylation at the tetraline ring, hydroxylation at the phenyl rings attached to tetraline, methylation of the catechol intermediates by catechol-O-methyl transferase, conjugation with glucuronic acid and sulfuric acid, and oxidation at the pyrrolidine ring. All the human metabolites were observed in at least one of the species (Prakash et al, 2008). In addition, the exposure of major circulating metabolites in these test species was higher relative to humans at proposed therapeutic doses, suggesting that the preclinical test species were suitable models for assessing safety (http:// www.fda.gov/cder/guidance/index.htm).…”

Section: Discussionmentioning

confidence: 99%

“…Based on its clearance values, it is likely that first pass hepatic metabolism is largely responsible to the attenuation of moderate bioavailability in rats (25%) and monkeys (55%). In humans, LAS is eliminated by both phase I oxidative metabolism mediated primarily by CYP3A4 and CYP2D6 isozymes and by phase II conjugation (Prakash et al, 2008). Metabolic pathways of drug candidates in animals, used for safety evaluation studies, are required to ensure that the selected animal species are exposed to all major metabolites (Ͼ10% parent AUC) formed in humans (Baillie et al, 2002; http:// www.fda.gov/cder/guidance/index.htm).…”

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confidence: 99%

Metabolism, Distribution, and Excretion of a Next Generation Selective Estrogen Receptor Modulator, Lasofoxifene, in Rats and Monkeys

Prakash

Johnson²,

Schroeder³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Disposition of lasofoxifene (LAS; 6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydro-naphthalen-2-ol. tartrate) was investigated in rats and monkeys after oral administration of a single oral dose of [ 14 C]LAS. Total mean recoveries of the radiocarbon were 96.7 and 94.3% from rats and monkeys, respectively. The major route of excretion in both species was the feces, and based on a separate study in the bile duct-cannulated rat, this likely reflects excretion in bile rather than incomplete absorption. Whole-body autoradioluminography suggested that [ 14 C]LAS radioequivalents distributed rapidly in the rat with most tissues achieving maximal concentrations at 1 h. Half-life of radioactivity was longest in the uvea (124 h) and shortest in the spleen (ϳ3 h). LAS was extensively metabolized in both rats and monkeys because no unchanged drug was detected in urine and/or bile. Based on area under the curve (0-24) values, >78% of the circulating radioactivity was due to the metabolites. A total of 22 metabolites were tentatively identified by liquid chromatography-tandem mass spectrometry. Based on the structures of the metabolites, six metabolic pathways of LAS were identified: hydroxylation at the tetraline ring, hydroxylation at the aromatic ring attached to tetraline, methylation of the catechol intermediates by catechol-O-methyl transferase, oxidation at the pyrrolidine ring, and direct conjugation with glucuronic acid and sulfuric acid. LAS and its glucuronide conjugate (M7) were the major circulating drug-related moieties in both rats and monkeys. However, there were notable species-related qualitative and quantitative differences in the metabolic profiles. The catechol (M21) and its sulfate conjugate (M10) were observed only in monkeys, whereas the glucuronide conjugate of the methylated catechol (M8) and hydroxy-LAS (M9) were detected only in rats.

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“…Oxidation of lasofoxifene is primarily catalyzed by CYP3A4/3A5 and CYP2D6 and leads to the formation of isomeric phenols followed by conjugation ( Figure A.10 ) (Prakash et al, 2008 ).…”

Section: A62 Polymorphism Of Dme Smentioning

confidence: 99%

Appendix: Drug Metabolizing Enzymes and Biotransformation Reactions

2012

ADME‐Enabling Technologies in Drug Design and Development

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Disposition of Lasofoxifene, a Next-Generation Selective Estrogen Receptor Modulator, in Healthy Male Subjects

Abstract: Postmenopausal women have an increased risk of developing osteoporosis as their levels of endogenous estrogen decrease (Luisetto et al

Cited by 17 publications

References 33 publications

Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol

Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Forms Reactive Quinones Similar to Estradiol

Metabolism, Distribution, and Excretion of a Next Generation Selective Estrogen Receptor Modulator, Lasofoxifene, in Rats and Monkeys

Appendix: Drug Metabolizing Enzymes and Biotransformation Reactions

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