In vitro metabolism studies

The carbon-fluorine bond is relatively resistant to metabolism. In vitro studies with rabbit, rat, and human hepatic microsomes and rat hepatocytes (Olson and Surbrook 1991 Olson et al. 1990a, 1990b) identified the major route of metabolism of HFC-134a as oxidation by P-450 2E1 to 2,2,2,1-tetrafluoroethanol elimination of hydrogen fluoride or fluoride ion yields 2,2,2-trifluoroacetaldehyde, which is further oxidized to trifluoroacetic acid. 

Useful data for the hazard assessment may also be obtained from studies on toxicokinetics (including metabolism), in vitro studies on macromolecule binding, from knowledge of the reactivity and electrophilicity of a substance, and from the presence or absence of structural alerts for genotoxicity. 

Metabolism - In vitro studies in human liver microsomes indicate that ertapenem does not inhibit metabolism mediated by any of the following cytochrome P450 (CYP) isoforms 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4. 

Metabolism - In vitro studies showed that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. P.982... 

Delavirdine reduces CYP3A activity and inhibits its own metabolism. In vitro studies have also shown that delavirdine reduces CYP2C9 and CYP2C19 activity. Inhibition of CYP3A by delavirdine is reversible within 1 week after discontinuation of the drug. 

Okadaic acid (OA) class compounds were shown to exert other biological effects, such as on metabolism, muscle contraction, secretion, and biosynthesis of different molecules. Considering the effects on the metabolism, in vitro studies revealed that OA can influence the metabolism of glucose and that of lipids.Glucose metabolism can be affected by the toxin through inhibition of glycogen... 

Compounds of this type have considerable biochemical interest because they may explain the antiketogenic action of D-glucose in preventing the X formation of ketone bodies during animal metabolism. In vitro studies have shown that the oxidation of the ester of acetoacetic acid by hydrogen peroxide proceeds much more rapidly in the presence of D-glucose than in its absence 187),... 

In vitro studies in human liver fractions indicated that azacitidine may be metabolized by the liver. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. 

In the case of dmg interactions involving metabolic inhibition, little increase in the substrate concentration is expected when the inhibition constant (K ) determined in in vitro studies using human liver samples is larger than the inhibitor concentration in vivo. Various approaches have been adopted using mathematical models in attempts to quantitatively predict in vivo dmg interactions from in vitro data [5]. 

However, very recent studies by Fish and his co-workers (467) with butyltin compounds showed that the primary, metabolic reaction is not Sn-C bond-cleavage but carbon hydroxylation of the n-butyl group. Using [l- C]tetrabutyltin in an in vitro study, the major, primary metabolite was identified as a 2-hydroxybutyltributyltin derivative that underwent a rapid /3-elimination reaction to afford 1-butene and a tri-butyltin compound (467). 

Tricyclohexyltin hydroxide is metabolized in vivo to inorganic tin via di- and monocyclohexyltin derivatives (502), and in vitro studies suggested that the major, metabolic reaction is carbon-hydroxylation of the cyclohexyl group (503). Studies in vivo using either tri-phenyl[ Sn]tin acetate (467) or triphenyl[" Sn]tin chloride (504) in rats showed that these compounds are metabolized to yield substantial amounts of di- and monophenyltin derivatives, although no significant quantities of hydroxylated metabolites have been identified (503) in this case. 

The available information in humans regarding the metabolism of methyl parathion is limited to in vitro studies (Hollingworth et al. 1973). However, the in vitro (Benke and Murphy 1975 Benke et al. 1974 Hollingworth et al. 1973 Nakatsugawa et al. 1968 Neal and DuBois 1965) metabolic pathway of this chemical has been characterized in animals. 

Distribution and Metabolic Fate—In Vivo and In Vitro Studies... 

X] 3 for human variability (pups represent a sensitive subpopulation the factor of 3 accounts for variation in the metabolism of trichloroethylene which was shown to be less than 10-fold in an in vitro study [Lipscomb et al. 1997])... 

At the moment, only three in vitro studies have been performed on Bfx metabolic behavior, hi one case, it has been shown that Bfxs are able to be reduced by oxyhemoglobin to the corresponding o-nitroaniline derivatives (Scheme 5) [237]. hi the reaction between compoimd 135 and oxyhemoglobin compound 136 was generated as secondary product resulting from both nitrile hydrolysis and deoxygenation. This study indicates that blood is a possible site for metabolism of Bfxs with the consequent methemoglobinemia. 

Parmentier Y, Bossant M-J, Bertrand M, Walther B (2006) In vitro studies of drug metabolism. In Taylor JB, Triggle DJ (eds) Comprehensive medicinal chemistry II. Elsevier, Oxford, Sect 5.10... 

Only a small number of drug interactions have been reported with donepezil. In vitro studies show a low rate of binding of donepezil to cytochrome P-450 (CYP)3A4 or 2D6. Whether or not donepezil has the potential for enzyme induction is not known. No interactions with theophylline, cimeti-dine, warfarin, digoxin, or ketoconazole have been documented. In vitro studies show that inhibitors of CYP3A4 and 2D6 have the potential to inhibit the metabolism of donepezil. The clinical relevance of this is unknown. However, monitoring for possible increased peripheral side effects is advised... 

In vitro studies have shown that memantine produces minimal inhibition of CYP450 enzymes CYP1A2, 2A6, 2C9,2D6, 2E1, and 3A4. These data indicate that no pharmacokinetic interactions with drugs metabolized by these enzymes should be expected.38... 

Organ clearances are usually based on in vivo rather than in vitro studies. Drug metabolic parameters, Vm and Km, can be estimated from in vitro hepatic enzyme and hepatocyte preparations [53], Knowledge of total clearance and fractional... 

As mentioned previously, in the AMD retina iron metabolism is compromised (He et al., 2007 Wong et al., 2007). Thus, it is of interest to determine the effects of potential antioxidants in the presence of iron. In an in vitro study of ARPE-19 cells, addition of a lipophilic iron complex led to about a ninefold increase in the photosensitized yield of 7a,(3-cholesterol hydroperoxides (Wrona et al., 2004). In the presence of the iron, ascorbate exerted pro-oxidant effects, while the effects of a-tocopherol, zeaxanthin, or their combination were still protective (Wrona et al., 2004). Thus, it appears that the effects of potential antioxidants are strongly dependent on the sources of oxidative damage. The same antioxidant may be protective under certain conditions and exert deleterious effects when the conditions are changed. Therefore a detailed understanding of the sources of the oxidative damage is required in order to design an adequate antioxidant mixture. 

Hamza, M., Lloveras,J., Ribbes, G., Soula, G. and Douste-Blazy, L. (1983) An in vitro study of hemicholinium-3 on phospholipid metabolism of Krebs II ascites cells. Biochemical Pharmacology 32, 1893—1897. 

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]. 

Naesens, L., Clercq, E. de, Van den Mooter, G., Kinget, R., Augustijns, P., Inhibition of intestinal metabolism of the antiviral ester prodrug bis(POC)-PMPA by nature-identical fruit extracts as a strategy to enhance its oral absorption an in vitro study, Pharm. Res. 1999, 16, 1035-1040. 

Moss, J., Bundgaard, FI., Prodrugs of peptides 8. In vitro study of intestinal metabolism and penetration of thyrotropin-releasing hormone (TRH) and its prodrugs, Int. J. Pharm. 1990, 66, 39-45. 

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