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Coadministered Drugs (coadministered + drug)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Prediction of herb,drug metabolic interactions: a simulation study

PHYTOTHERAPY RESEARCH, Issue 6 2005
Shufeng Zhou
Abstract In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb,drug interactions. An attempt was made to simulate the effects of herbal preparation with single or multiple CYP-inhibiting constituents on the area of the plasma concentration-time curve (AUC) of coadministered drug that was either a low clearance drug by intravenous (i.v.) injection or a high clearance drug by oral route. Our simulation studies indicated that the expected increase (Rc) in the AUC of the coadministered drug by inhibiting herbal constituent(s) was dependent on the route of administration. For low clearance drug by i.v. injection, Rc was generally determined by inhibition constant (Ki), unbound inhibitor concentration ([I]), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm), while Rc for a high clearance drug by oral route, Rc was determined by Ki, [I], n and fm. By varying these parameters, Rc changed accordingly. It appeared likely to predict a herb,drug metabolic interaction, if the inhibiting herbal constituents could be quantitatively determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and thus in vivo animal and human studies are always necessary. Copyright © 2005 John Wiley & Sons, Ltd. [source]

In vitro effects of tacrolimus on human cytochrome P450

FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2002
K. Lecointre
Abstract Tacrolimus, a potent immunosuppressive drug, is known to be metabolized predominantly in the liver by cytochrome P450 3A (CYP3A). In order to determine the potential of tacrolimus to inhibit the metabolism of other drugs, we have investigated its inhibitory effects on specific cytochrome reactions. Specific substrates for the seven cytochromes (CYPs) 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4/5 were incubated with human hepatic microsome preparations with or without specific inhibitors or tacrolimus and the metabolites were detected by high-pressure liquid chromatography (HPLC) or fluorimetric methods. All the specific inhibitors reduced or abolished the specific CYP activity. Tacrolimus had no effect on any CYP at concentrations below 1 µm, while at higher concentrations it had a mild inhibitory effect on CYP3A4 and 3A5. These observations suggest that tacrolimus is unlikely to potentiate the effect of coadministered drugs through inhibition of their metabolism in the liver. [source]

Chemoresistant tumor cell lines display altered epidermal growth factor receptor and HER3 signaling and enhanced sensitivity to gefitinib

INTERNATIONAL JOURNAL OF CANCER, Issue 12 2008
Tiziana Servidei
Abstract Deregulated signaling through the epidermal growth factor receptor (EGFR) is involved in chemoresistance. To identify the molecular determinants of sensitivity to the EGFR inhibitor gefitinib (Iressa, ZD1839) in chemoresistance, we compared the response of matched chemosensitive and chemoresistant glioma and ovarian cancer cell lines. We found that chemoresistant cell lines were 2- to 3-fold more sensitive to gefitinib growth-inhibitory effects, because of decreased proliferation rather than survival. Sensitivity to gefitinib correlated with overexpression and constitutive phosphorylation of HER2 and HER3, but not EGFR, altered HER ligand expression, and enhanced activation of EGF-triggered EGFR pathway. No activating mutations were found in EGFR. Gefitinib fully inhibited EGF-induced and constitutive Akt activation only in chemoresistant cells. In parallel, gefitinib downregulated constitutively phosphorylated HER2 and HER3, and activated GSK3, with a concomitant degradation of cyclin D1. Ectopically overexpressed HER2 on its own was insufficient to sensitize chemonaive cells to gefitinib. pHER3 coimmunoprecipitated with p85-PI3K in chemoresistant cells and gefitinib dissociated these complexes. siRNA-mediated inhibition of HER3 decreased constitutive activation of Akt and sensitivity to gefitinib in chemoresistant cells. Our study indicates that in chemoresistant cells gefitinib inhibits both an enhanced EGF-triggered pathway and a constitutive HER3-mediated Akt activation, indicating that inhibition of HER3 together with that of EGFR could be relevant in chemorefractory tumors. Furthermore, in combination experiments gefitinib enhanced the effects of coadministered drugs more in chemoresistant than chemosensitive ovarian cancer cells. Combined treatment might be therapeutically beneficial in chemoresistant tumors from ovary and likely from other tissues. © 2008 Wiley-Liss, Inc. [source]

Role of drug metabolism in drug discovery and development

MEDICINAL RESEARCH REVIEWS, Issue 5 2001
Gondi N. Kumar
Abstract Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. High metabolic lability usually leads to poor bioavailability and high clearance. Formation of active or toxic metabolites will have an impact on the pharmacological and toxicological outcomes. There is also potential for drug,drug interactions with coadministered drugs due to inhibition and/or induction of drug metabolism pathways. Hence, optimization of the metabolic liability and drug,drug interaction potential of the new chemical entities are some of the most important steps during the drug discovery process. The rate and site(s) of metabolism of new chemical entities by drug metabolizing enzymes are amenable to modulation by appropriate structural changes. Similarly, the potential for drug,drug interactions can also be minimized by appropriate structural modifications to the drug candidate. However, the optimization of the metabolic stability and drug,drug interaction potential during drug discovery stage has been largely by empirical methods and by trial and error. Recently, a lot of effort has been applied to develop predictive methods to aid the optimization process during drug discovery and development. This article reviews the role of drug metabolism in drug discovery and development. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 397,411, 2001 [source]