O Modelo CPN-1 Não-Comutativo em (2+1)D

Rodrigues, Alexandre Guimarães

doi:10.11606/t.43.2003.tde-21062012-160558

Cited by 4 publications

(4 citation statements)

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“…In addition, a taurine conjugate of ibuprofen was identified in the urine of humans as a minor metabolite (Shirley et al, 1994). (S)-Naproxen was metabolized by CYP2C9, CYP1A2, UGT2B7, and SULT1A1 (Rodrigues et al, 1996;Bowalgaha et al, 2005;Falany et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes

et al. 2012

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ABSTRACT:Prediction of human drug metabolism is important for drug development. Recently, the number of new drug candidates metabolized by not only cytochrome P450 (P450) but also non-P450 has been increasing. It is necessary to consider species differences in drug metabolism between humans and experimental animals. We examined species differences of drug metabolism, especially between humans and rats, for ibuprofen and (S)-naproxen as nonsteroidal anti-inflammatory drugs, which are metabolized by P450 and UDP-glucuronosyltransferase, sulfotransferase, and amino acid N-acyltransferase for taurine conjugation in liver, using human chimeric mice (h-PXB mice) repopulated with human hepatocytes and rat chimeric mice (r-PXB mice) transplanted with rat hepatocytes. We performed the direct comparison of excretory metabolites in urine between h-PXB mice and reported data for humans as well as between r-PXB mice and rats after administration of ibuprofen and (S)-naproxen. Good agreement for urinary metabolites (percentage of dose) was observed not only between humans and h-PXB mice but also between rats and r-PXB mice. Therefore, the metabolic profiles in humans and rats reflected those in h-PXB mice and r-PXB mice. Our results indicated that h-PXB mice should be helpful for predicting the quantitative metabolic profiles of drugs mediated by P450 and non-P450 in liver, and r-PXB mice should be helpful for evaluation of species differences in these metabolic enzymes.

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Section: Discussionmentioning

confidence: 99%

Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes

et al. 2012

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“…Zileuton also has a minimal effect on the oral clearance (ϳ8% decrease) of naproxen (Awni et al, 1995b). This is expected, because naproxen is largely metabolized by glucuronidation (ϳ70%), and there are no reports that zileuton is an inhibitor of UDP-glucuronosyltransferases in vivo (Rodrigues et al, 1996). At the same time, the O-demethylation of naproxen is catalyzed by CYP2C9 and CYP1A2, but the overall contribution of each enzyme to overall clearance is low (f m ⅐ f m,P450 ϳ0.15).…”

Section: Discussionmentioning

confidence: 99%

Mechanism-Based Inhibition of Human Liver Microsomal Cytochrome P450 1a2 by Zileuton, a 5-Lipoxygenase Inhibitor

Lü¹,

Schrag²,

Slaughter³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Zileuton, a 5-lipoxygenase inhibitor, was evaluated as an inhibitor of cytochrome P450 activity in human liver microsomes. In the absence of preincubation, the racemate was found to be a weak inhibitor (IC 50 > 100 M) of phenacetin O-deethylation (POD) (CYP1A2), paclitaxel 6␣-hydroxylation (CYP2C8), diclofenac 4-hydroxylation (CYP2C9), (S)-mephenytoin 4-hydroxylation (CYP2C19), bufuralol 1-hydroxylation (CYP2D6), testosterone 6␤-hydroxylation (CYP3A4), chlorzoxazone 6-hydroxylation (CYP2E1), and bupropion hydroxylation (CYP2B6). When preincubated with NADPH-fortified human liver microsomes in the absence of substrate, zileuton (racemate) was shown to inhibit POD. The effect was NADPH-, time-, and concentration-dependent, and was characterized by a k inact (maximal rate of enzyme inactivation) and apparent K I (inhibitor concentration that supports half the maximal rate of inactivation) of 0.035 min ]. In addition, the inhibition of CYP1A2 was not reversed in the presence of reduced glutathione, catalase, and superoxide dismutase and was refractory to dialysis. Therefore, zileuton was characterized as a mechanism-based inhibitor of human liver microsomal CYP1A2. Mechanism-based inhibition of CYP1A2 may explain why zileuton decreases the oral clearance of antipyrine, propranolol, (R)-warfarin, and theophylline, at doses that have a minimal effect on the pharmacokinetics of (S)-warfarin, phenytoin, and terfenadine. Zileuton (Zyflo;thien-2-ylethyl)-N-hydroxyurea), a substituted hydroxamic acid, is a potent and selective 5-lipoxygenase inhibitor that has been approved for the prevention and chronic treatment of asthma (Isreal et al., 1990;Carter et al., 1991;Bell et al., 1992;Wenzel and Kamada, 1996;Dube et al., 1999). The drug contains a single chiral center (Fig. 1), is administered as a racemic mixture of (R)-(ϩ)-and (S)-(Ϫ)-enantiomers, and is characterized by a plasma half-life of about 4 h (Wong et al., 1995). As a result of the short half-life, zileuton has to be dosed four times a day (q.i.d.), and effective inhibition (70 -80%) of leukotriene B 4 biosynthesis can be attained using a 600-mg q.i.d. dosing regimen (Awni et al., 1995a).Zileuton is well absorbed, and the majority of the dose (ϳ75%) is recovered in the urine of healthy volunteers as the N-hydroxy glucuronides of both the (R)-(ϩ)-and (S)-(Ϫ)-enantiomers (Wong et al., 1995). Although N-hydroxy glucuronidation has been confirmed with human liver microsomes, zileuton is metabolized in the presence of NADPH (Machinist et al., 1995b;Sweeny and Nellans, 1995). In fact, CYP1A2 and CYP2C9 catalyze ring hydroxylation, whereas sulfoxidation is catalyzed largely by CYP3A4. Both reactions conform to Michaelis-Menten kinetics in human liver microsomes and are described by relatively high K m values (Ն 0.2 mM).Zileuton also has been shown to be a weak inhibitor of human liver microsomal CYP3A4, CYP2C9, and CYP2D6 activity in vitro (Machinist et al., 1995b). As anticipated, zileuton has a m...

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“…CYP2C9 is one of the major human hepatic cytochrome P450 isoforms, and it is responsible for the metabolism of several commonly used drugs, such as (S)-warfarin (Rettie et al, 1992), phenytoin, tolbutamide (Veronese et al, 1991), and a number of nonsteroidal anti-inflammatory drugs (Zhao et al, 1992;Leemann et al, 1993;Rodrigues et al, 1996;Tracy et al, 1996). In addition, polymorphic variants of CYP2C9 have been identified as being expressed in several human populations.…”

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confidence: 99%

Polymorphic Variants of CYP2C9: Mechanisms Involved in Reduced Catalytic Activity

Lian

Locuson²,

Tracy³

2007

Mol Pharmacol

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CYP2C9 catalyzes the demethylation of the biphasic kinetics substrate (S)-naproxen, and the CYP2C9*2 (R144C) and CYP2C9*3 (I359L) variants are associated with lower rates of (S)-naproxen demethylation. To assess the reasons for these reductions in catalytic activity of the two variants and potential substrate concentration-dependent differences in a biphasic kinetics substrate, cytochrome P450 (P450) cycle coupling and uncoupling were monitored during coincubation of (S)-naproxen and CYP2C9 over a range of P450 reductase concentrations. Coupling was greatest in the CYP2C9.1 enzyme, followed by CYP2C9.2, and then CYP2C9.3. Uncoupling in CYP2C9.1 and CYP2C9.3 was primarily to H 2 O 2 . In contrast, CYP2C9.2 uncoupled to excess water preferentially. The conversion of enzyme to the high spin state was similar in CYP2C9.1 and CYP2C9.2, but lower in CYP2C9.3. It is noteworthy that neither altered substrate binding nor altered interaction with reductase seemed to be involved in reduced catalysis. These results suggest that in addition to coupling differences, differential uncoupling to shunt products and differences in spin state help explain the reduced catalytic activity in these enzymes.The cytochrome P450 (P450) enzymes are responsible for the biotransformation of a wide range of exogenous and endogenous substrates (Wrighton and Stevens, 1992). P450-mediated metabolism occurs via a catalytic cycle (Scheme 1) that involves several steps: 1) substrate binding; 2) oneelectron addition to the substrate-P450 complex by CPR; 3) oxygen binding to the ferrous P450; 4) transfer of a second electron by either CPR or cytochrome b 5 and protonation of the resulting iron-peroxo anion intermediate; 5) cleavage of the O-O bond to generate H 2 O; 6, 7) oxidation of the substrate; and 8) and release of product with subsequent

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O Modelo CPN-1 Não-Comutativo em (2+1)D

Cited by 4 publications

References 0 publications

Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes

Predictability of Metabolism of Ibuprofen and Naproxen Using Chimeric Mice with Human Hepatocytes

Mechanism-Based Inhibition of Human Liver Microsomal Cytochrome P450 1a2 by Zileuton, a 5-Lipoxygenase Inhibitor

Polymorphic Variants of CYP2C9: Mechanisms Involved in Reduced Catalytic Activity

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