Metabolic activation, in vitro

Table 5.28 The Effect of Allylisopropylacetamide (AIA) on Cytochrome P-450 and Drug-Metabolizing Activity In Vitro and Pharmacological Activity In Vivo...

TABLE 5.25 Effect of allylisopropylacetamide (AIA) on cytochrome P-450 and drug metabolizing activity in vitro and pharmacological activity in vivo... 

Adiotomre, Eastwood, M. A. Edwards, C. A. Brydon, W. G. (1990). Dietary fiber in vitro methods that anticipate nutrition and metabolic activity in humans. American Journal of Clinical Nutrition, Vol.52, No.l, Qanuary 1990), pp. 128-134, ISSN 0002-9165. 

Magee, P.N. in de Serres, F.J., Fouts, J.R., Bend, J.R. and Philpot, R.M. (eds), In Vitro Metabolic Activation in Mutagenesis Testing , Elsevier/North Holland Biomedical Press, Amsterdam, 1976 pp. 213-216. 

Srinivas RV, Robbins BL, Connelly MC, Gong Y-F, Bischofberger N, Frid-land A. Metabolism and in vitro antiretroviral activities of bis(pivaloylox-ymethyl) prodrugs of acyclic nucleoside phosphonates. Antimicrob Agents Chemother 1993 37 2247-2250. 

Chauret, N., Gauthier, A. and Nicoll-Griffth, D.A. (1998) Effect of common solvents on in vitro cytochrome P450 mediated metabolic activities in human liver microsomes. Drug Metabolism and Disposition The Biological Fate of Chemicals, 26, 1-4. 

The 3-ketothiolase has been purified and investigated from several poly(3HB)-synthesizing bacteria including Azotobacter beijerinckii [10], Ral-stonia eutropha [11], Zoogloea ramigera [12], Rhodococcus ruber [13], and Methylobacterium rhodesianum [14]. In R. eutropha the 3-ketothiolase occurs in two different forms, called A and B, which have different substrate specificities [11,15]. In the thiolytic reaction, enzyme A is only active with C4 and C5 3-ketoacyl-CoA whereas the substrate spectrum of enzyme B is much broader, since it is active with C4 to C10 substrates [11]. Enzyme A seems to be the main biosynthetic enzyme acting in the poly(3HB) synthesis pathway, while enzyme B should rather have a catabolic function in fatty-acid metabolism. However, in vitro studies with reconstituted purified enzyme systems have demonstrated that enzyme B can also contribute to poly(3HB) synthesis [15]. 

Mehorta and coworkers (1989) observed that isolated fractions of brain and heart cells from rats orally administered 0.5-10 mg endrin/kg showed significant inhibition of Ca+2 pump activity and decreased levels of calmodulin, indicating disruption of membrane Ca+2 transport mechanisms exogenous addition of calmodulin restored Ca+2-ATPase activity. In vitro exposure of rat brain synaptosomes and heart sarcoplasmic reticuli decreased total and calmodulin-stimulated calcium ATPase activity with greater inhibition in brain preparations (Mehorta et al. 1989). However, endrin showed no inhibitory effects on the calmodulin-sensitive calcium ATPase activity when incubated with human erythrocyte membranes (Janik and Wolf 1992). In vitro exposure of rat brain synaptosomes to endrin had no effect on the activities of adenylate cyclase or 3, 5 -cyclic phosphodiesterase, two enzymes associated with synaptic cyclic AMP metabolism (Kodavanti et al. 1988). 

Spaldin, V., Madden, S., Adams, D.A., Edwards, R.J., Davies, D.S. and Park, B. K. (1995) Determination of human hepatic cytochrome P4501A2 activity in vitro use of tacrine as an isoenzyme-specific probe. Drug Metabolism and Disposition, 23 (9), 929-934. 

Dibromoethane tested positive for mutagenicity with or without metabolic activation in fungi and mammalian cell lines in in vitro assay systems (Brimer et al. 1982 Clive et al. 1979 ... 

Much information on the mechanism of action and cross-resistance of purine analogues has been obtained in bacteria, some of which are quite sensitive to certain of these compounds in vitro. There is a great deal of variation in response of the various bacteria to a particular agent and of a particular bacterium to the various cytotoxic purine analogues. Some, if not most, of these differences are probably due to differences in the anabolism of the various compounds. Despite the fact that certain purine analogues have quite a spectrum of antibacterial activity in vitro, none has been useful in the treatment of bacterial infections in vivo because their toxicity is not selective—the metabolic events whose blockade is responsible for their antibacterial activity are also blocked in mammalian cells and thus inhibition of bacterial growth can only be attained at the cost of prohibitive host toxicity. In contrast, the sulpha drugs and antibiotics such as penicillin act on metabolic events peculiar to bacteria. 

In vitro genotoxic studies have given positive results for gene mutations, chromosomal aberrations, DNA damage, and cell transformation in the presence of metabolic activation in vivo assays have generally been negative. ... 

Mutagenesis Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in 1 of 5 bacterial strains. Oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. 

Irinotecan has demonstrated a broad spectrum of activity in vitro and in vivo, and synergistic effects have been observed when it is administered in combination with other antineoplastic agents. Clinically irinotecan is now an active agent in patients with colorectal carcinoma. Irinotecan is metabolized by carboxylesterase to an active metabolite. It is cleared by hepatic metabolism and biliary excretion with a terminal elimination half-life of approximately 15 hours. The principal toxicities associated with irinotecan are diarrhoea and leucopenia. 

Waller, G. R. and M. F. Roberts. N-methyltransferases and 7-methyl-N-nucleoside hydrolase activity in vitro of Coffea arabica fruits, and the biosynthesis of caffeine , and the in vivo metabolism of caffeine. Proc lUPAC 11th International Symp Chem Nat Prod 1978 4(2) 55-71. 

Famciclovir is the diacetyl ester prodrug of 6-deoxypencidovir, an acyclic guanosine analog (Figure 49-2). After oral administration, famciclovir is rapidly deacetylated and oxidized by first-pass metabolism to penciclovir. It is active in vitro against HSV-1, HSV-2, VZV, EBV, and HBV. As with acyclovir, activation by phosphorylation is catalyzed by the virus-specified thymidine kinase in infected cells, followed by competitive inhibition of the viral DNA polymerase to block DNA synthesis. Unlike acyclovir, however, penciclovir does not cause chain termination. Penciclovir triphosphate has lower affinity for the viral DNA polymerase than acyclovir triphosphate, but it achieves higher intracellular concentrations. The most commonly encountered clinical mutants of HSV are thymidine kinase-deficient these are cross-resistant to acyclovir and famciclovir. 

Vinylidene fluoride is taken up rapidly via the pulmonary route in rats, but at equilibrium the mean concentration (by volume) in rats was only 23% of that in the gaseous phase. Metabolism proceeded very slowly and was saturable at exposure concentrations of about 260 mg/m Its maximum rate was 1% that of vinyl chloride and less than 20% that of vinyl fluoride there has been a report of an increase in the urinary excretion of fluoride in exposed rats. No alkylating intermediate was demonstrated after passage through a mouse-liver microsomal system. However, vinylidene fluoride inhibits mixed-function oxidase activity in vitro and, like similar halogenated compounds that are transformed to reactive metabolites, it alters rat intermediary metabolism, leading to acetone exhalation (lARC, 1986). 

Zang et al [140] reported the liver protective effects of the saponins isolated from A. membranaceus and A. sieversianus against chemical injury induced by CCU, D-galactosamine and acetaminophen in mice. In all cases there were positive activities and the saponins inhibited the rise in SGPT levels, decreased the malondialdehyde (MDA) content and increased the glutathione reduced (GSH) concentration in mouse liver. The same compounds were also evaluated in cultured rat hepatocytes, and the results indicated that the activity may be due to to the antioxidative activity of the saponins, since the content of liver protein in treated mice was more than the control. Moreover, in all treated mice, the level of hepatic microsomal cytochrome P-450 was increased. The liver metabolism and immunoregulating action produced by saponins may be also involved in their hepato-protective effects. Similar results were obtained by Zhang et al [141] when they studied the activity in vitro and... 

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