Evaluation of the effects of dietary n-3 fatty acid supplementation on the pharmacokinetics of doxorubicin in dogs with lymphoma.

Objective: To determine the effect of dietary n-3 fatty acids on the pharmacokinetics of doxorubicin in dogs with lymphoma.

Animals: 23 dogs with lymphoma in stages IIIa, IVa, and Va.

Procedure: Dogs receiving doxorubicin chemotherapy were randomly allocated to receive food with a high (test group) or low (control group) content of n-3 fatty acids.

Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer.

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have demonstrated antitumor activity in patients with non-small-cell lung cancer (NSCLC). This study examined the safety profile of the monoclonal antibody EGFR inhibitor, cetuximab, when added to paclitaxel and carboplatin in untreated patients with stage IV NSCLC. Secondary objectives included efficacy and paclitaxel and carboplatin pharmacokinetics during cetuximab treatment.

Rapid and sensitive LC/MS/MS analysis of the novel tyrosine kinase inhibitor ZD6474 in mouse plasma and tissues.

ZD6474 (N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy] quinazolin-4-amine) is a tyrosine kinase inhibitor with anti-angiogenic and anti-tumor activity that is currently undergoing human trials for cancer treatment. Pharmacokinetic studies in animal models are an important component in clinical development of this agent to relate pre-clinical models to patient treatment. A liquid chromatography tandem mass spectrometry method was developed for the determination of ZD6474 levels in mouse plasma and tissues.

P450 induction alters paclitaxel pharmacokinetics and tissue distribution with multiple dosing.

Purpose: Paclitaxel (Taxol) is an effective agent against a broad range of human cancers. Studies on the metabolism and disposition of paclitaxel have shown that it is primarily eliminated via hepatic metabolism by P450 enzymes (2C8 and 3A4) to essentially inactive metabolites, and that biliary and gut transport by P-glycoprotein (PGP) as well as urinary elimination of the parent compound play relatively minor roles. Recent studies in vitro have shown that paclitaxel treatment increases the level of CYP2C8 and CYP3A4 in human hepatocytes as well as PGP in colon tumor cells.

Pharmacokinetics of combined doxorubicin and paclitaxel in mice.

Doxorubicin (DOX) has excellent antitumor activity when combined with paclitaxel (PTX) and this combination is used as first-line treatment for metastatic breast cancer. Results from clinical studies on pharmacokinetic interaction of these agents are not conclusive and pre-clinical studies are still needed. Pharmacokinetic studies were carried out in female Balb/c mice with combined DOX (6 mg/kg) and PTX (10 mg/kg) treatment.

A phase I and pharmacokinetic study of exisulind and docetaxel in patients with advanced solid tumors.

Purpose: Exisulind (sulindac sulfone, FGN-1, Aptosyn) is a sulindac metabolite that induces apoptosis via inhibition of cyclic GMP-phosphodiesterase. This agent demonstrated tumor growth inhibition in rodent models of colon, breast, prostate, and lung carcinogenesis. In an orthotopic model of human non-small-cell lung cancer, the combination of exisulind and docetaxel prolonged survival in athymic nude rats, forming the basis of this phase I combination study.

Analysis of docetaxel pharmacokinetics in humans with the inclusion of later sampling time-points afforded by the use of a sensitive tandem LCMS assay.

Purpose: Docetaxel is a semisynthetic taxane derived from the needles of the European yew ( Taxus baccata) and it is an important chemotherapeutic agent in the treatment of recurrent ovarian, breast and non-small-cell lung cancers. Traditional dosing regimens with docetaxel involve doses of 60-100 mg/m(2) by infusion every 3 weeks. Now weekly low-dose (30-36 mg/m(2)) regimens are being evaluated in phase I trials.

Stochastic simulation of hepatic preneoplastic foci development for four chlorobenzene congeners in a medium-term bioassay.

A combination of experimental and simulation approaches was used to analyze clonal growth of glutathione-S-transferase pi (GST-P) enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen for 1,4-dichlorobenzene (DCB), 1,2,4,5-tetrachlorobenzene (TECB), pentachlorobenzene (PECB), and hexachlorobenzene (HCB). Male Fisher 344 rats, eight weeks of age, were initiated with a single dose (200 mg/kg, ip) of diethylnitrosamine (DEN). Two weeks later, daily dosing of 0.

Kinetics of NAD(P)H:quinone oxidoreductase I (NQO1) inhibition by mitomycin C in vitro and in vivo.

The bioreductive activation of the antitumor quinone mitomycin C (MMC) by NAD(P)H: quinone oxidoreductase 1 (NQO1) is complicated by the ability of MMC to also act as a mechanism-based inhibitor of NQO1 in a pH dependent manner. Inhibition of NQO1 by MMC has been studied in purified enzyme preparations and in cultured cells but has not determined in vivo. In the studies presented here, NQO1 activity was measured in mouse tissues following treatment with MMC or the potent mechanism-based human NQO1 inhibitor 5-methoxy-1,2-dimethyl-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936).

Doxorubicin pharmacokinetics: Macromolecule binding, metabolism, and excretion in the context of a physiologic model.

The studies described herein were designed to determine whether doxorubicin (DOX) pharmacokinetics (PKs) could be described by a physiologically based PK model that incorporated macromolecule-specific binding and organ-specific metabolism and excretion. Model parameters were determined experimentally, or were gathered from the literature, in a species-specific manner, and were incorporated into a physiologically based description of DOX blood and tissue distribution for mice, dogs, and humans. The resulting model simulation data were compared with experimentally determined data using PK parameters calculated using compartmental or noncompartmental analysis to assess the predictability of the models.