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Saquinavir mesylate (SQV) is the first-in-class and prototypical HIV protease inhibitor (PI) used in the treatment of HIV infection. SQV undergoes extensive hepatic metabolism and intestinal and bile secretion, and has poor and variable oral bioavailability. In previous studies, our group and others have described the interactions between SQV and absorptive(More)
PURPOSE To investigate the role of intestinal breast cancer resistant protein (BCRP) in the absorption and disposition of topotecan (TPT) using novobiocin (NOV) as a specific inhibitor. METHODS Transporter inhibition specificity of NOV was assessed in cells overexpressing BCRP or Pgp. Sprague-Dawley rats were orally or intravenously dosed with TPT (2 and(More)
The neuropeptide galanin (GAL) is up-regulated following neuronal axotomy or inflammation. Since other neuropeptides act as immunomodulatory agents, we sought to determine whether GAL might affect the murine microglial cell line BV2, which expresses the GAL2 receptor. Even at very low concentrations, GAL inhibited tumor necrosis factor-alpha (TNF alpha)(More)
It has been shown that the human acute lymphoblastic leukemia (ALL) T cell line (RPMI 8402) selected with irinotecan (CPT-11) is transformed to a multidrug resistant (MDR) phenotype (CPT-K5) with cross-resistance to mitoxantrone (MX). Since MX is a well-documented substrate for the efflux transporter breast cancer resistant protein (BCRP/ABCG2), we assessed(More)
In this case study, in vitro and in vivo data were provided for saquinavir (SQV) showing that drug transporters play a significant role in the absorption and disposition of drugs. This article is focused on the more practical points with a technical emphasis. Currently many in vitro and in vivo experimental models have been developed to investigate drug(More)
The development of drugs that act in the CNS has been significantly impeded by the difficulty of delivering them across the blood-brain barrier (BBB). This article aims to provide the reader with a critical overview of important issues in the discovery and development of drugs that need to enter the brain to elicit pharmacological activity, focusing(More)
Penetration of epithelial cells represents the rate-determining step for the absorption of many drugs and pharmaceutical macromolecules such as proteins and nucleic acid therapeutics. While the potential of using cell-penetrating peptides (CPPs) to facilitate absorption has been increasingly recognized, the mechanism of cell penetration and the uptake into(More)
Agents antagonizing the anti-apoptotic Bcl-2 protein have been shown to restore normal apoptotic processes in cancer cells. Since upregulation of Bcl-2 is often observed in recurrent or refractory hematological malignancies, we were prompted to investigate whether drug-selected leukemia cells overexpressing Bcl-2 were more susceptible to Bcl-2 antagonists.(More)
The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in(More)
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