Mary B Sauer

Bristol-Myers Squibb, New York, New York, United States

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Publications (4)4.07 Total impact

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    ABSTRACT: Monkeys have been proposed as an animal model to predict the magnitude of human clinical drug-drug interactions caused by CYP3A4 enzyme induction. To evaluate whether the cynomolgus monkey can be an effective in vivo model, human CYP3A4 inducers were evaluated both in vitro and in vivo. First, a full-length pregnane X receptor (PXR) was cloned from the cynomolgus monkey, and the sequence was compared with those of rhesus monkey and human PXR. Cynomolgus and rhesus monkey PXR differed by only one amino acid (A68V), and both were highly homologous to human PXR (approximately 96%). When the transactivation profiles of 30 compounds, including known inducers of CYP3A4, were compared between cynomolgus and human PXR, a high degree of correlation with EC(50) values was observed. These results suggest that cynomolgus and human PXR respond in a similar fashion to these ligands. Second, two known human CYP3A4 inducers, rifampicin and hyperforin, were tested in monkey and human primary hepatocytes for induction of CYP3A enzymes. Both monkey and human hepatocytes responded similarly to the inducers and resulted in increased RNA and enzyme activity changes of CYP3A8 and CYP3A4, respectively. Lastly, in vivo induction of CYP3A8 by rifampicin and hyperforin was shown by significant reductions of midazolam exposure that were comparable with those in humans. These results show that the cynomolgus monkey can be a predictive in vivo animal model of PXR-mediated induction of human CYP3A4 and can provide a useful assessment of the resulting pharmacokinetic changes of affected drugs.
    Drug metabolism and disposition: the biological fate of chemicals 10/2009; 38(1):16-24. DOI:10.1124/dmd.109.029637 · 3.33 Impact Factor
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    ABSTRACT: Rats are used routinely for the discovery of new pharmaceuticals and for toxicology testing to fulfill regulatory requirements. In 1999, a survey showed that 80% of all rodents housed in toxicology studies were housed in wire-bottom cages. However, both the National Research Council and Association for the Assessment and Accreditation of Laboratory Animal Care, International, recommend housing rats in solid-bottom cages with bedding. In this study 2 groups of male Sprague Dawley rats were housed in the same room for 4 wk and provided the same food and water by the same husbandry staff person. The only variable in the study was the type of housing. One group was housed in solid-bottom polycarbonate cages with bedding and the other group in standard wire-bottom caging. Clinical pathology laboratory evaluations of complete blood count, serum chemistries, urinalysis, urine creatinine, urine corticosterone, blood coagulation, and hepatic cytochrome P450 isoenzyme mRNA levels were performed. No clinically relevant differences were found between the 2 groups for any of the laboratory data.
    Journal of the American Association for Laboratory Animal Science: JAALAS 02/2006; 45(1):30-5. · 0.73 Impact Factor
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    ABSTRACT: The common marmoset (Callithrix jacchus) has been used to study various therapeutic targets including cytokines, stroke, Parkinson's disease and behavior such as anxiety. Whereas most nonhuman primates (NHP) are expensive to maintain, difficult to handle and require large quantities of test material the marmoset is small (200 to 500g), relatively inexpensive, easy to handle, and can be kept socially with a high quality of life. These features offer advantages over other NHP models for pharmacokinetic (PK), drug-drug interaction (DDI) and pharmacokinetic/ pharmacodynamic (PK/PD) studies. However, one disadvantage to using marmosets has been the difficulty in collecting blood samples for analysis. Therefore we surgically implanted vascular access ports in male marmosets that greatly facilitated the administration of test compound and intravenous blood sample collection. For evaluation, midazolam was dosed in crossover studies by IV, PO at 1.5 mg/kg and 7.4 mg/kg and intranasal (IN) administration at 0.6 mg/kg: oral bioavailability was measured at 1.6 to 3.7% at 1.5 mg/kg PO and 4.9 to 11% at 7.4 mg/kg PO; intranasal bioavailability was 11 to 24% at 0.6 mg/kg IN. The 1'-OH and 4-OH midazolam metabolites were both measured in plasma with 1'-OH midazolam the major metabolite, which is similar to humans. The plasma clearance was 47 to 114 mL/min/kg which, when coupled with a lower oral bioavailability, suggests possibly a greater relative expression of CYP3A in the marmoset liver and/or gut than in humans. These studies show that the marmoset is a viable and novel alternative to other NHP models for conducting PK studies, with some associated advantages and disadvantages that will be discussed in the presentation.
    8th International International society for the study of xenobiotics Meeting;
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    ABSTRACT: Monkey has been proposed as an animal model to predict the magnitude of human drug-drug interactions caused by CYP3A4 enzyme induction. In order to evaluate whether cynomolgus monkey can be an effective model, multiple human CYP3A4 inducers were evaluated both in vitro and in vivo. First, cynomolgus monkey pregnane-X-receptor (PXR) was cloned and compared to rhesus monkey and human PXR sequences. Cynomolgus and rhesus PXR were different by only two base-pairs and highly homologous to human PXR (~96%). Next, the induction response of 30 compounds in a cynomolgus monkey PXR transactivation assay were compared to the assay employing human PXR. A good correlation of PXR activation in monkey and human PXR was observed, suggesting that both PXRs respond to human-specific ligands in a similar manner. Secondly, rifampicin and hyperforin were tested in monkey and human primary hepatocytes for the induction of CYP3A8 and CYP3A4, respectively. Again, cynomolgus monkey and human hepatocytes responded similarly to the inducers and resulted in increased RNA and enzyme activity changes of CYP3A. Lastly, in vivo induction of CYP3A8 in cynomolgus monkeys was demonstrated with rifampicin and hyperforin and resulted in a significant reduction of midazolam exposure comparable to the AUC reductions observed in human drug-drug interaction studies. Our results demonstrate that the cynomolgus monkey can be a predictive in vivo animal model of human CYP3A4 induction in vitro, as well as provide useful quantitative pharmacokinetic changes that occur in vivo.
    15th North American Regional International society for the study of xenobiotics Meeting;