21 research outputs found
Single Plasma Concentrations of 1âČâHydroxymidazolam or the Ratio of 1âČâHydroxymidazolam: Midazolam Do Not Predict Midazolam Clearance in Healthy Subjects
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97152/1/009127002237986.pd
Limited Sampling Strategy to Predict AUC of the CYP3A Phenotyping Probe Midazolam in Adults: Application to Various Assay Techniques
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97211/1/00912700222011418.pd
Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage
The International Stem Cell Initiative analyzed 125 human embryonic stem (ES) cell lines and 11 induced pluripotent stem (iPS) cell lines, from 38 laboratories worldwide, for genetic changes occurring during culture. Most lines were analyzed at an early and late passage. Single-nucleotide polymorphism (SNP) analysis revealed that they included representatives of most major ethnic groups. Most lines remained karyotypically normal, but there was a progressive tendency to acquire changes on prolonged culture, commonly affecting chromosomes 1, 12, 17 and 20. DNA methylation patterns changed haphazardly with no link to time in culture. Structural variants, determined from the SNP arrays, also appeared sporadically. No common variants related to culture were observed on chromosomes 1, 12 and 17, but a minimal amplicon in chromosome 20q11.21, including three genes expressed in human ES cells, ID1, BCL2L1 and HM13, occurred in >20% of the lines. Of these genes, BCL2L1 is a strong candidate for driving culture adaptation of ES cells
Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes.â Drug Metab Dispos 28(6
This paper is available online at http://www.dmd.or
Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models.
FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indirectly target both BCL-XL and MCL-1 through modulation of protein expression, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ acute myeloid leukemia preclinical models and provides strong mechanistic rational for clinical studies
Role of PâGlycoprotein on the Brain Penetration and Brain Pharmacodynamic Activity of the MEK Inhibitor Cobimetinib
Cobimetinib
is a MEK inhibitor currently in clinical trials as
an anticancer agent. The objectives of this study were to determine
in vitro and in vivo if cobimetinib is a substrate of P-glycoprotein
(P-gp) and/or breast cancer resistance protein (Bcrp1) and to assess
the implications of efflux on cobimetinib pharmacokinetics (PK), brain
penetration, and target modulation. Cell lines transfected with P-gp
or Bcrp1 established that cobimetinib was a substrate of P-gp but
not a substrate of Bcrp1. In vivo, after intravenous and oral administration
of cobimetinib to FVB (wild-type; WT), <i>Mdr1a/bÂ(â/â)</i>,<i> Bcrp1 (â/â)</i>, and <i>Mdr1a/bÂ(â/â)/BcrpÂ(â/â)</i> knockout (KO) mice, clearance was similar in WT (35.5 ± 16.7
mL/min/kg) and KO animals (22.0 ± 3.6 to 27.6 ± 5.2 mL/min/kg);
oral exposure was also similar between WT and KO animals. After an
oral 10 mg/kg dose of cobimetinib, the mean total brain to plasma
ratio (Kp) at 6 h postdose was 0.3 and 0.2 in WT and <i>Bcrp1Â(â/â)</i> mice, respectively. In <i>Mdr1a/bÂ(â/â)</i> and <i>Mdr1<i>a</i>/1b/Bcrp1Â(â/â)</i> KO mice and WT mice treated with elacridar (a P-gp and BCRP inhibitor),
Kp increased to 11, 6, and 7, respectively. Increased brain exposure
in <i>Mdr1a/bÂ(â/â)</i> and <i>Mdr1<i>a</i>/1b/Bcrp1Â(â/â)</i> KO and elacridar
treated mice was accompanied by up to âŒ65% suppression of the
target (pErk) in brain tissue, compared to WT mice. By MALDI imaging,
the cobimetinib signal intensity was relatively high and was dispersed
throughout the brain of <i>Mdr1<i>a</i>/1b/Bcrp1Â(â/â)</i> KO mice compared to low/undetectable signal intensity in WT mice.
The efflux of cobimetinib by P-gp may have implications for the treatment
of patients with brain tumors/metastases