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BACKGROUND AND OBJECTIVES Gefitinib (IRESSA, ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, has been approved in several countries for the treatment of advanced non-small-cell lung cancer. Preclinical studies were conducted to determine the cytochrome P450 (CYP) isoenzymes involved in the metabolism of gefitinib and to evaluate the(More)
Methapyrilene (MP), a 2-thiophene H(1)-receptor antagonist, is a model toxicant in the genomic and proteomic analyses of hepatotoxicity. In rats, it causes an unusual periportal necrosis that is hypothetically attributed to chemically reactive and cytotoxic metabolites. We have characterized the bioactivation of MP by hepatic microsomes and primary rat(More)
OBJECTIVES AND DESIGN Measurement of phosphorylated zidovudine (ZDV) inside infected cells is more likely to provide satisfactory dose response relationships than serum concentrations. This study provides information on ZDV phosphorylation in HIV-seronegative volunteers (n = 5) and in patients with HIV infection (n = 12). METHODS Intracellular ZDV(More)
1. Zidovudine (3'-azido-2',3'-dideoxythymidine; AZT; ZDV) is a dideoxynucleoside analogue active against human immunodeficiency virus (HIV). We are currently investigating the intracellular metabolism of ZDV to its putative active triphosphate form (ZDV triphosphate) in peripheral blood mononuclear cells and a lymphoblastoid cell line (h1A2v2). 2. Optimal(More)
Human breast cancer cells are used extensively for the study of steroid hormone action. It is known that in both receptor positive and receptor negative cell lines there is considerable metabolism of the natural estrogens, estradiol (E2) and estrone (E1) with interconversion of the two steroids and formation of sulphate and glucuronide conjugates. The aim(More)
The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small(More)
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to(More)
Drug reactivity and bioactivation are of major concern to the development of potential drug candidates in the pharmaceutical industry (Chem Res Toxicol 17:3-16, 2004; Chem Res Toxicol 19:889-893, 2006). Identifying potentially problematic compounds as soon as possible in the discovery process is of great importance, so often early in vitro screening is used(More)