TY - JOUR
T1 - Pharmacokinetics of the estrogen receptor subtype-selective ligands, PPT and DPN
T2 - Quantification using UPLC-ES/MS/MS
AU - Sepehr, Estatira
AU - Lebl-Rinnova, Marketa
AU - Mann, Meagan K.
AU - Pisani, Samantha L.
AU - Churchwell, Mona I.
AU - Korol, Donna L.
AU - Katzenellenbogen, John A.
AU - Doerge, Daniel R.
N1 - Funding Information:
The authors acknowledge funding from Grant Number P50AT006268 to J.A.K. and D.R.D. from NIH, NIA, NCCAM, ODS, and NCI , as well as R37DK015556 to J.A.K. and NSF IOB 0520876 and IOS 1118414 to D.L.K. ES acknowledges support of a fellowship from the Oak Ridge Institute for Science and Education, administered through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The authors have no conflicts of interest to report. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration.
PY - 2012/12
Y1 - 2012/12
N2 - Estrogen receptor (ER) subtype specific agonists, diarylpropionitrile (DPN) for ERβ and propylpyrazoletriol (PPT) for ERα, are pharmacological probes used frequently to define mechanisms for estrogen actions in vitro and in vivo. Quantitative analytical methodology was developed and validated for DPN and PPT, based on synthetic stable labeled analogs (DPN-d4 and PPT-d5) using isotope dilution liquid chromatographic tandem electrospray mass spectrometric detection. The validated method produced high sensitivity, with detection limits of 0.04-0.07ng/ml serum. Serum pharmacokinetics were evaluated in Long-Evans rats following a single subcutaneous injection (2mg/kg bw) of both compounds. The role of Phase II metabolism was evaluated using β-glucuronidase and arylsulfatase hydrolysis to measure total DPN and PPT in addition to the parent compounds. The pharmacokinetic properties of DPN and PPT reported could facilitate experimental designs requiring specified levels of receptor occupancy for quantitative comparisons of ER subtype specificities for natural and synthetic estrogens in vivo.
AB - Estrogen receptor (ER) subtype specific agonists, diarylpropionitrile (DPN) for ERβ and propylpyrazoletriol (PPT) for ERα, are pharmacological probes used frequently to define mechanisms for estrogen actions in vitro and in vivo. Quantitative analytical methodology was developed and validated for DPN and PPT, based on synthetic stable labeled analogs (DPN-d4 and PPT-d5) using isotope dilution liquid chromatographic tandem electrospray mass spectrometric detection. The validated method produced high sensitivity, with detection limits of 0.04-0.07ng/ml serum. Serum pharmacokinetics were evaluated in Long-Evans rats following a single subcutaneous injection (2mg/kg bw) of both compounds. The role of Phase II metabolism was evaluated using β-glucuronidase and arylsulfatase hydrolysis to measure total DPN and PPT in addition to the parent compounds. The pharmacokinetic properties of DPN and PPT reported could facilitate experimental designs requiring specified levels of receptor occupancy for quantitative comparisons of ER subtype specificities for natural and synthetic estrogens in vivo.
KW - Estrogen receptor subtypes
KW - Isotope dilution quantification
KW - Mass spectrometry
KW - Pharmacokinetics
KW - Synthetic deuterium labeling
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U2 - 10.1016/j.jpba.2012.08.022
DO - 10.1016/j.jpba.2012.08.022
M3 - Article
C2 - 22981216
AN - SCOPUS:84866774346
SN - 0731-7085
VL - 71
SP - 119
EP - 126
JO - Journal of Pharmaceutical and Biomedical Analysis
JF - Journal of Pharmaceutical and Biomedical Analysis
ER -