Dmd063735 1392..1407
نویسندگان
چکیده
Thirty-three Collies (14 male and 19 female) were used in a doseescalation study to determine the impact of ABCB1 genotype on loperamide pharmacokinetics (PK) and pharmacodynamics (PD). Loperamide was orally administered in four ascending doses (0.01, 0.05, 0.1, or 0.2 mg/kg) over a 4-wk period to fasted Collies. Comparisons were made within each dose to genotype, phenotype, and whether Collies received three (3D) or four (4D) loperamide doses. The 3D and 4D groupings had statistically significant differences in systemic drug exposure (defined by the area under the concentration-versus-time profile estimated from time zero to the last quantifiable drug concentration, AUC0–last). In contrast, statistical differences in AUC0–last only occurred in the comparison between wild-type (WT) Collies versus homozygous mutant (Mut) Collies administered 0.1 mg/kg. Statistical differences in the proportionality relationship were observed when comparing 3D to 4D Collies, and the WT to Mut Collies. Intersubject variability in drug exposure tended to be twice as high between Mut and WT Collies. Associations were observed between systemic drug exposure and ataxia or depression but not between systemic drug exposure and mydriasis or salivation. Thus, Collies expressing the greatest sensitivity to CNS-associated effects of loperamide (Mut) tended to have higher drug exposure compared with those less sensitive to the adverse effects of loperamide. Genotype and phenotype only partially explained differences in loperamide PK and PD, suggesting this relationship may not be straightforward and that other factors need to be considered. Accordingly, the PD and PK of one P-glycoprotein substrate only partially predicted the likelihood of adverse responses to unrelated substrates.
منابع مشابه
DNA hybridization electron microscopy: ribosomal RNA nucleotides 1392-1407 are exposed in the cleft of the small subunit.
The ribosomal sequence corresponding to Escherichia coli 16S rRNA nucleotides 1392-1407 (the "1400 region") is phylogenetically conserved and is in a functionally important region of the subunit. Using the technique of DNA hybridization electron microscopy, we have mapped this sequence on the surface of the small ribosomal subunit. In this procedure a synthetic oligodeoxynucleotide probe, compl...
متن کاملNovel cyclic peptide agonist of high potency and selectivity for the type II vasoactive intestinal peptide receptor.
Ro 25-1392 [Ac-Glu8,OCH3-Tyr10,Lys12,Nle17,Ala19,A sp25,Leu26,-Lys27,28-vasoactive intestinal peptide(cyclo 21-25)] is a cyclic peptide analog of vasoactive intestinal peptide (VIP) that potently exerts cellular effects typical of VIP. The selectivity of Ro 25-1392 for type I (VIPR1) and type II (VIPR2) VIP receptors was investigated first in competitive binding studies using Chinese hamster ov...
متن کاملThe early - type galaxies NGC 1407 and NGC 1400 − I : spatially resolved radial kinematics and surface photometry
This is the first paper of a series focused on investigating the star formation and evolutionary history of the two early-type galaxies NGC 1407 and NGC 1400. They are the two brightest galaxies of the NGC 1407 (or Eridanus-A) group, one of the 60 groups studied as part of the Group Evolution Multi-wavelength Study (GEMS). Here we present new high signal-to-noise long-slit spectroscopic data ob...
متن کاملAn imaging study of the globular cluster systems of NGC 1407 and NGC
We present wide-field Keck telescope imaging of the globular cluster (GC) systems around NGC 1407 and NGC 1400 in the Eridanus galaxy cloud. This is complemented by Hubble Space Telescope images from the Advanced Camera for Surveys of NGC 1407 and Wide Field and Planetary Camera 2 images of NGC 1400. We clearly detect bimodality in the GC colour distribution of NGC 1407. The blue GC subpopulati...
متن کامل