Absolute bioavailability of letrozole in healthy postmenopausal women

Sioufi, A.; Gauducheau, N.; Pineau, V.; Marfil, F.; Jaouen, A.; Cardot, J; Godbillon, J.; Czendlik, C.; Howald, H.; Pfister, C.; Vreeland, F.

doi:10.1002/(sici)1099-081x(199712)18:9<779::aid-bdd64>3.3.co;2-x

Cited by 25 publications

(41 citation statements)

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“…For letrozole, a high f m of 0.80 was selected, based on reports that at least 85% of a letrozole dose is eliminated by P450-mediated metabolism, with CYP2A6 being the enzyme responsible for approximately 93% of metabolism at therapeutic letrozole concentrations. The low f m of 0.31 was selected based on in vitro studies of letrozole metabolism involving microsomes with reduced CYP2A6 activity (Sioufi et al, 1997;Murai et al, 2009;Desta et al, 2011). Based on our literature searches, the systemic t-CA concentration in human blood following oral administration has yet to be reported.…”

Section: Downloaded Frommentioning

confidence: 99%

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

Chan¹,

Oshiro²,

Thomas³

et al. 2016

Drug Metabolism and Disposition

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Human exposure to trans-cinnamic aldehyde [t-CA; cinnamaldehyde; cinnamal; (E)-3-phenylprop-2-enal] is common through diet and through the use of cinnamon powder for diabetes and to provide flavor and scent in commercial products. We evaluated the likelihood of t-CA to influence metabolism by inhibition of P450 enzymes. IC 50 values from recombinant enzymes indicated that an interaction is most probable for CYP2A6 (IC 50 = 6.1 mM). t-CA was 10.5-fold more selective for human CYP2A6 than for CYP2E1; IC 50 values for P450s 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4 were 15.8-fold higher or more. t-CA is a type I ligand for CYP2A6 (K S = 14.9 mM). Inhibition of CYP2A6 by t-CA was metabolism-dependent; inhibition required NADPH and increased with time. Glutathione lessened the extent of inhibition modestly and statistically significantly. The carbon monoxide binding spectrum was dramatically diminished after exposure to NADPH and t-CA, suggesting degradation of the heme or CYP2A6 apoprotein. Using a static model and mechanism-based inhibition parameters (K I = 18.0 mM; k inact = 0.056 minute 21

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Section: Downloaded Frommentioning

confidence: 99%

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

Chan¹,

Oshiro²,

Thomas³

et al. 2016

Drug Metabolism and Disposition

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“…1. Letrozole is metabolized to a carbinol metabolite, which undergoes subsequent glucuronidation (Sioufi et al, 1997;Murai et al, 2009;Lazarus and Sun, 2010); the UGT isoform involved in carbinol glucuronidation (UGT2B7) was identified in this study.…”

Section: Western Blot Analysis Of Ugt2b7 Expression In Hlmsmentioning

confidence: 81%

“…1). Carbinol-gluc [bis(4-cyanophenyl)methyl hexopyranosiduronic acid] is the major metabolite of letrozole, its amount in urine accounting for 65% of the total dose of administered drug (Sioufi et al, 1997;Pfister et al, 2001). Toward our goal, we used metabolic screening with a battery of recombinant human UGTs and a panel of human liver microsomes (HLMs), as well as correlative and inhibition experiments.…”

Section: Introductionmentioning

confidence: 99%

The Letrozole Phase 1 Metabolite Carbinol as a Novel Probe Drug for UGT2B7

et al. 2013

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Carbinol [4,49-(hydroxymethylene)dibenzonitrile] is the main phase 1 metabolite of letrozole, a nonsteroidal aromatase inhibitor used for endocrine therapy in postmenopausal breast cancer. We elucidated the contribution of UDP-glucuronosyltransferase (UGT) isoforms on the glucuronidation of carbinol. Identification of UGT isoforms was performed using a panel of recombinant human UGT enzymes. Kinetic studies were done in recombinant human UGT2B7 and pooled human liver microsomes (HLMs). A liquid chromatography-tandem mass spectrometry method was used for detection of metabolites.To assess the impact of UGT2B7*2, we determined the carbinol glucuronidation activity using HLM as well as UGT2B7 protein expression in 148 human livers. Moreover, we analyzed the plasma concentrations of 60 letrozole-treated breast cancer patients. We identified UGT2B7 as the predominant UGT isoform involved in carbinol glucuronidation. In HLMs and recombinant UGT2B7, we determined K m values (9.99 and 9.56 mM) and V max values (3430 and 2399 pmol/min per milligram of protein), respectively. In the set of 148 human livers, carbinol glucuronidation activity significantly correlated with UGT2B7 protein as determined by Western blotting (r s = 0.5088, P < 0.0001). Neither carbinol glucuronidation activity (*1/*1: n = 25, 2434 6 1018; *1/*2: n = 80, 2356 6 1372; *2/*2: n = 43, 2251 6 1421 pmol/min per milligram of protein) nor UGT2B7 protein expression was altered by the UGT2B7*2 genotype. No impact of UGT2B7*2 on plasma levels of carbinol and carbinol-gluc [bis(4-cyanophenyl)methyl hexopyranosiduronic acid] in 60 letrozole-treated patients was found. Taken together, these findings suggest carbinol as a novel in vitro probe substrate for UGT2B7. In vitro and in vivo data suggest a lack of influence of the UGT2B7*2 polymorphism on carbinol glucuronidation.

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“…Letrozole prevents the aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit. In the previously published literature the bio-analytical methods for determining letrozole in human plasma were found tedious, lengthy process and also was not cost effective [2][3][4]. In the present study a LC-MS/MS-ESI method was developed for detection and quantification of letrozole in human plasma.…”

Section: Introductionmentioning

confidence: 94%

Bioanalytical Method Development and Validation of Letrozole by LC-ESI-MS/MS in Human Plasma

Pal¹

2017

JAPLR

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Letrozole (CAS Number-112809-51-5) is widely used as an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery. For quantitation of letrozole, negative polarity was used to achieve adequate response because this was highly sensitive for compounds with high electron affinity. It was applied to fragment the analytes and to obtain intense and consistent product ions. The deprotonated precursor ions [M-H]−at m/z 284.1 was observed in Q1(MS) for letrozole. Characteristic product ions found in Q3(MS) was at m/z 242. 0, 102.1, 126.7, 140.7, 215.1, 240.3 for letrozole. Most stable and consistent fragment ion selected m/z 242.0 having the triazole ring. For the internal standard (tolbutamide) the fragment at Q1 and Q3 having m/z 269.1 and 170.1 was responsible for possessing the methoxyethyl-phenoxy group. In the present study LC-MS/MS-ESI method was attempted to develop for detection and quantification of letrozole in human plasma.Therefore, it can be concluded from the present study findings that developed method by using LC-MS/MS API 2000 and liquid-liquid extraction technique for letrozole in human plasma was found to be simple, specific, sensitive, reproducible and fully validated in according to EMA and USFAD guidelines. The present method was found superior enough to be applied to comparative pharmacokinetic studies in future.

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Absolute bioavailability of letrozole in healthy postmenopausal women

Cited by 25 publications

References 0 publications

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

Inactivation of CYP2A6 by the Dietary Phenylpropanoid trans-Cinnamic Aldehyde (Cinnamaldehyde) and Estimation of Interactions with Nicotine and Letrozole

The Letrozole Phase 1 Metabolite Carbinol as a Novel Probe Drug for UGT2B7

Bioanalytical Method Development and Validation of Letrozole by LC-ESI-MS/MS in Human Plasma

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