4.
eCollection 2020. Please enable it to take advantage of the complete set of features! (1997).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. Down-regulation of PXR and CAR is likely one of the mechanisms for UGT- suppression by high concentrations of IL-6, whereas AhR may be involved in TNFα-mediated UGT-suppression. doi: 10.1371/journal.pone.0239540. | NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. Conversely, dog liver microsomes had significant lower activities of CYP2B and CYP2D than those of cats. Addition of 2% BSA to the incubation with both P450 and UGT cofactors reduced the bias in the clearance prediction, with 8 of 10 compounds predicted within 2-fold of in vivo values with the exception of raloxifene and gemfibrozil. The inhibitor ketoconazole was proven to be specific for human and dog CYP3A (Newton et al., 1995; Kuroha et al., 2002; Lu et al., 2005). These UGTs features were taken into account in DDI Predict 2009® Edition to increase prediction accuracy.
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00. The ultimate goal of biotransformation processes is to convert a substance into metabolites, which are less active than the parent compound or even inactive, less lipid‐soluble, more polar and more suitable for elimination by renal and/or biliary excretion (for review see: Anzenbacher & Anzenbacherova, 2001; Fink‐Gremmels, 2008; Nebert & Russell, 2002; Zuber et al., 2002). The protein concentrations of the microsomal fractions were determined by the method of Lowry using BSA (bovine serum albumin) as a standard (Lowry et al., 1951). A shift in the chemical space that medicinal chemists are interrogating has led to generally more polar drug molecules, which has in turn has caused an increase in the prevalence of non-cytochrome P450 metabolic pathways. The results of the incubation of single enantiomers generally agreed with the chiral analyses of mono-OH-M derived from the glucuronidase digestion of the glucuronides of the racemic mono-OH-M. The structures of the glucuronides were identified by liquid chromatography/tandem mass spectometry.
The structures of the glucuronides were identified by liquid chromatography/tandem mass spectometry. The conditions determined from this first study were applied to several substrates with multiple metabolic pathways and varying degrees of AO clearance. Copyright © 2020 by the American Society for Pharmacology and Experimental Therapeutics, Sign In to Email Alerts with your Email Address.
Moreover, IC50‐values of cat CYPs differed from dog and human CYPs underlining the interspecies differences. The substrates for these isozymes were 3‐cyano‐7‐ethoxycoumarin (CEC), 7‐ethoxy‐4‐trifluoromethylcoumarin (EFC), dibenzylfluorescein (DBF), 3‐[2‐(N,N‐diethyl‐N‐methylamino)ethyl]‐7‐methoxy‐4‐methylcoumarin (AMMC), 7‐methoxy‐4‐trifluoromethylcoumarin (7‐MFC) and 7‐benzyloxy‐4‐(trifluoromethyl)‐coumarin (BFC) respectively. The drug-metabolizing enzymes that contribute to the metabolism or bioactivation of a drug play a crucial role in defining the absorption, distribution, metabolism, and excretion properties of that drug.
| However, by HPLC a very low activity of tolbutamide hydroxylase, indicating CYP2C9 in humans, was found in cats and dogs (Chauret et al., 1997; Shah et al., 2007).
Sallustio BC, Sabordo L, Evans AM, Nation RL. Rats treated with the same dose of CP 1 day prior to killing showed a significant decrease in microsomal morphine-UGT activity at 0.05 and 2.5 mM morphine, but a significant increase in activity was observed following administration of CP or Adriamycin (AD; 10 mg/kg) 4 days prior to killing. In clinical practice, the lower CYP activities in cats, combined with the low glucuronidation capacity will result in longer half‐lives of many drugs that undergo extensive biotransformation reactions. Therap. Influence of dietary Coexposure to benzo(a)pyrene on the biotransformation and distribution of 14C-methoxychlor in the channel catfish (Ictalurus punctatus). Interestingly, the predicted CLlung using rat lung microsomes corresponded to approximately 35% of rat CLliver suggesting that the lung makes a smaller contribution to the whole body clearance of benzydamine.
When CYP2C9 only represents a small part of the total CYP2C activity, the other two isozymes are able to convert the substrate and as a consequence no numerical decline in CYP2C activity will be found in the presence of a specific inhibitor.
We are pleased to present a second annual issue highlighting a previous year’s literature on biotransformation and bioactivation. About
Epub 2009 Jan 29.
Yamasaki C, Ishida Y, Yanagi A, Yoshizane Y, Kojima Y, Ogawa Y, Kageyama Y, Iwasaki Y, Ishida S, Chayama K, Tateno C. PLoS One. CYP2D activity was hardly detectible in the liver microsomes of all animal species and these findings are in accordance with previous investigations (Chauret et al., 1997; Shimada et al., 1997). For estradiol-3-glucuronidation and lamotrigine–N2-glucuronidation, no obvious modulation was observed.
Experimental paradigms, based on the use of human liver microsomes (HLM), hepatocytes, and recombinant UGTs as the enzyme
We found that in cat, dog and human liver microsomes CYP2C activity was inhibited by tranylcypromine and quercetine. Functional expression and comparative characterization of four feline P450 cytochromes using fluorescent substrates. Thermal inactivation of FMO and CYP inhibition suggested that rat pulmonary N-oxygenation is predominantly FMO mediated while any contribution from CYPs is negligible. Hepatic disposition of electrophilic acyl glucuronide conjugates.
It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a Ki value of 3.61 μM. M2 formation was found independent of NADPH, and the level was 9-fold higher in S9 incubations, as compared to that of microsomal incubations.
To obtain IC50 values, different concentrations of specific inhibitors of the human CYP isozymes were added to the liver microsomes of both species. Other investigations confirm these gender differences in cytochrome activity although only for the isozymes CYP2D and CYP3A (Shah et al., 2007). In dogs, these activities were high as well but comparable to the chlorzoxazone 6‐hydroxylase activity (CYP2E) (Chauret et al., 1997) and also the aniline p‐hydroxylation (CYP2E), benzphetamine N‐demethylation and nifedipine oxidation (CYP3A) (Shimada et al., 1997).
The second group is the utilization of preparations of the drug metabolizing enzymes such as supersomes, cytochrome P450, cytosolic fraction, S9 fraction, human liver microsomes and rat liver microsomes.
The most striking difference was found in the oxidation of 7‐MFC (CYP2E), as cats seem to have a 12‐fold lower activity compared to dogs and an 8‐fold lower activity compared to humans.
It was found that in dogs, bufuralol‐1‐hydroxylase activity, associated with CYP2D, was comparable with human CYP2D activity, albeit being lower than in other animals (Sharer et al., 1995; Roussel et al., 1998; Bogaards et al., 2000). Although benzydamine clearance in rat appears to be predominantly mediated by hepatic metabolism, the data suggests that the lung may also make a smaller contribution to its whole body clearance. Moreover, ketoprofen was more actively metabolized through glucuronide conjugates by fresh chimeric hepatocytes than by cryopreserved cells.
Keywords: Metabolite identification, drug discovery & development, toxicology, cellular models, metabolizing enzymes. The activities associated with CYP3A and CYP2B were higher than the activities of the other measured CYPs. Curr Drug Metab. For example, similar CYP3A activities were found in male rat liver microsomes and human liver microsomes with respect to the 6‐hydroxylation of dexamethasone (Tomlinson et al., 1997).