Model metabolite-inhibition

Pygeum africanum, an extract from the bark of the African prune tree, has been used in Europe since 1969 to treat men with mild to moderate symptoms of benign prostatic hyperplasia. The mechanism of action of P. africanum is not known. In animal models, P. africanum modulates bladder contractility, has anti-inflammatory activity, decreases production of leukotrienes and other 5-lipoxygenase metabolites, inhibits fibroblast production, affects adrenal androgens, and restores the secretory activity of prostate epithelium. 

The model response plotted in Figure 2 is based on the following metabolite-inhibition mechanism (6)... 

Figure 2. Heparin data and metabolite-inhibition model for three separate injections of drug. (-----) heparin concentration (O) experimental data (--------) me-...

Some metabolites of curcumin (particularly tetrahydrocurcumin) may also participate in producing the observed effects of curcumin in different models because these metabolites display greater stabilities than the parent curcumin molecule at physiological pH. Recent data show similar modes of action of curcumin metabolites regarding antioxidant enzyme induction and inhibition of multidrug-resistant proteins. " Additional data indicate that curcumin may even act against other types of diseases such as atherosclerosis " " and Alzheimer s disease. " - " ... 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

The Influence of DNA Structure and Environment on the Intercalation of Hydrocarbon Metabolites and Metabolite Model Compounds. The physical binding of hydrocarbon metabolites to DNA is very sensitive to DNA structure and environment. This is demonstrated by the data in Figures 4 and 5, which show how heat denaturation of DNA inhibits hydrocarbon quenching. These results are consistent with early studies which indicate that the ability of native DNA to solubilize pyrene and BP is much greater than that of denatured DNA (40). 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

Figure 30. A medium complexity model of yeast glycolysis [342], The model consists of nine metabolites and nine reactions. The main regulatory step is the phosphofructokinase (PFK), combined with the hexokinase (HK) reaction into a single reaction vi. As in the minimal model, we only consider the inhibition by its substrate ATP, although PFK is known to have several effectors. External glucose (Glc ) and ethanol (EtOH) are assumed to be constant. Additional abbreviations Glucose (Glc), fructose 1,6 biphosphate (FBP), pool of triosephosphates (TP), 1,3 biphosphogly cerate (BPG), and the pool of pyruvate and acetaldehyde (Pyr).

Compound A appears mainly as unchanged drug in the bile whereas compound B appears partly as metabolites. Administration of ketoconazole, a potent cytochrome P450 inhibitor, to the preparation dramatically decreases the metabolism of B and the compound appears mainly as unchanged material in the bile. Despite the inhibition of metabolism, hepatic extraction remains high (0.9). This indicates that clearance is dependent on hepatic uptake, via a transporter system, for removal of the compounds from the circulation. Metabolism of compound B is a process that occurs subsequent to this rate-determining step and does not influence overall clearance. This model for the various processes involved in the clearance of these compounds is illustrated in Figure 5.4. 

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