Tamoxifen therapy reduced platelet counts without change in platelet function

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109840/1/cptclpt2005247.pd

Stereoselective pharmacokinetics of stable isotope (+/-)-[13C]-pantoprazole: Implications for a rapid screening phenotype test of CYP2C19 activity

AIMS: We have previously shown that the (±)-[(13) C]-pantoprazole breath test is a promising noninvasive probe of CYP2C19 activity. As part of that trial, plasma, breath test indices and CYP2C19 (*2, *3, and *17) genotype were collected. Here, we examined whether [(13) C]-pantoprazole exhibits enantioselective pharmacokinetics and whether this enantioselectivity is correlated with indices of breath test. METHODS: Plasma (-)- and (+)-[(13) C]-pantoprazole that were measured using a chiral HPLC were compared between CYP2C19 genotypes and correlated with breath test indices. RESULTS: The AUC( 0-∞) of (+)-[(13) C]-pantoprazole in PM (*2/*2, n = 4) was 10.1- and 5.6-fold higher that EM (*1/*1or *17, n = 10) and IM (*1/*2or *3, n = 10) of CYP2C19, respectively (P < 0.001). The AUC( 0-∞) of (-)-[(13) C]-pantoprazole only significantly differed between PMs and EMs (1.98-fold; P = 0.05). The AUC( 0-∞) ratio of (+)-/(-)-[(13) C]-pantoprazole was 3.45, 0.77, and 0.67 in PM, IM, and EM genotypes, respectively. Breath test index, delta over baseline show significant correlation with AUC( 0-∞) of (+)-[(13) C]-pantoprazole (Pearson's r = 0.62; P < 0.001). CONCLUSIONS: [(13) C]-pantoprazole exhibits enantioselective elimination. (+)-[(13) C]-pantoprazole is more dependent on CYP2C19 metabolic status and may serve as a more attractive probe of CYP2C19 activity than (-)-[(13) C]-pantoprazole or the racemic mixture

Menopausal status and estrogen receptor genotypes influenced the severity of hot flashes after tamoxifen treatment

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109844/1/cptclpt200521.pd

Gene expression profiles of 4‐hydroxy‐N‐desmethyl‐tamoxifen (endoxifen)‐ and 4‐hydroxy‐tamoxifen (4OHTAM)‐treated human breast cancer cells determined by CDNA microarray analysis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109798/1/cptclpt2004192.pd

Pii‐21

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109873/1/cptclpt2006159.pd

CYP genotypes influence the effect of tamoxifen therapy on serum lipids

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110066/1/cptclpt2004270.pd

Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons

Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000nmol of adenosine 5'-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats

ER‐alpha and ER‐beta genotypes predict tamoxifen effects on serum lipids in breast cancer patients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110087/1/cptclpt200418.pd

Pi‐29

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110026/1/cptclpt200664.pd