Cytochromes P-450 in rats: structures, functions, properties and relevant human forms

Souček, Pavel; Gut, Ivan

doi:10.3109/00498259209053106

Cited by 221 publications

(96 citation statements)

References 154 publications

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“…46 Sequential homologies of CYPs (including CYP3A) between rats and humans are also high (more than 70%); there are generally conserved regions (for cytochrome P450 reductase, heme, and signal peptide) that increase this similarity. 47 Thus, these in situ and in vivo rat data may predict the intestinal absorption and oral bioavailability of docetaxel in humans.…”

Section: F1mentioning

confidence: 99%

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Cho¹,

Park²,

Yoon³

et al. 2014

IJN

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Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel.

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Section: F1mentioning

confidence: 99%

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Cho¹,

Park²,

Yoon³

et al. 2014

IJN

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“…The aims of the present study are to compare P450 inhibition properties in both rat microsomes and freshly isolated hepatocytes following corrections for the projected unbound drug within the incubation, to make an assessment of the inhibitor concentration within the hepatocyte, and to identify the relative contributions of intracellular binding and active transport. To this end, tolbutamide and phenytoin, dextromethorphan and midazolam, were studied as appropriate P450 probes for the rat P450s in the CYP2C, CYP2D, and CYP3A families, respectively (Soucek and Gut, 1992;Kobayashi et al, 2003;Chovan et al, 2007), with kinetic and inhibition studies performed for each compound.…”

mentioning

confidence: 99%

Use of Isolated Hepatocyte Preparations for Cytochrome P450 Inhibition Studies: Comparison with Microsomes forK_iDetermination

Brown

Chadwick²,

Houston

2007

Drug Metab Dispos

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ABSTRACT:Predicting drug-drug interactions requires an assessment of the drug concentration available to the enzyme active site, both in vivo, and within an in vitro incubation. These predictions are confounded when the inhibitor accumulates within the liver, either as a result of active transport processes or intracellular binding (including lysosomal trapping). In theory, hepatocytes should provide a more accurate estimation of inhibitory potency compared with microsomes for those compounds that undergo hepatic accumulation. However, they are not routinely used for K i determination and there is limited comparative information available. Therefore, the aims of this study were to compare K i values determined in rat microsomes and freshly isolated hepatocytes using six cytochrome P450 inhibitors (miconazole, fluconazole, ketoconazole, quinine, fluoxetine, and fluvoxamine) with a range of uptake properties (cell-to-medium concentration ratios 4.2-6000). Inhibition studies were performed using four probe substrates for CYP2C, CYP2D, and CYP3A enzymes (tolbutamide and phenytoin, dextromethorphan and midazolam, respectively). Comparison of unbound K i values (range 0.05-30 M) showed good agreement between microsomes and hepatocytes for inhibition of 18 pathways of metabolism. In addition to this, there was no relationship between the cell-to-medium concentration ratios (covering over 3 orders of magnitude) and the microsomal to hepatocyte K i ratio of these inhibitors. These data suggest that the hepatic accumulation of these inhibitors results from intracellular binding rather than the involvement of uptake transporters and indicate that microsomes and hepatocytes appear to be equivalent for determining the inhibitory potency of the six inhibitors investigated in the present study.Quantitative prediction of drug-drug interactions (DDIs) requires an accurate estimation of drug concentration at the enzyme active site, both in vivo within the liver and within an in vitro incubation. Since it is impossible to directly measure this liver concentration in humans, plasma concentrations have been used as an in vivo surrogate, but with varying degrees of success (Ito et al., 2002(Ito et al., , 2004. Although the use of plasma inhibitor concentration has accurately predicted the degree of in vivo DDIs for several compounds (Brown et al., 2005(Brown et al., , 2006Obach et al., 2006), even the use of total plasma concentrations may underestimate hepatocellular concentrations for inhibitors that are accumulated within the liver.Drug can be sequestered within the hepatocyte via several mechanisms; for example, lysosomal uptake, intracellular protein binding, or the involvement of hepatic uptake transporters. Lysosomes represent 1% of the hepatocyte volume; therefore, trapping is an important distribution process for weak bases, which can accumulate within this compartment due to the pH gradient between the acidic lysosome compartment (pH 5), the hepatic cytosol (pH 7.2), and the plasma (pH 7.4) (Daniel, 2003). Drug accumulation...

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“…To investigate which isozymes of P450 give rise to MI complexes during the metabolism of 1 we turned to reconstituted systems with CYP2B1/2, the major isoforms in PB-microsomes, and with 2C11 and 2E1 which are constitutive isoforms in male rat liver [40]. To our surprise we observed no MIC formation from 1 with any of these reconstituted systems (Table 2).…”

Section: Resultsmentioning

confidence: 65%

Cyclopropylamine inactivation of cytochromes P450: Role of metabolic intermediate complexes

Cerny

Hanzlik

2005

Archives of Biochemistry and Biophysics

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, "Cyclopropylamine inactivation of cytochromes P450. Role of metabolic intermediate complexes." Arch. Biochem. Biophys. 436, 265-275 (2005). Keywords:Cytochrome P450, flavin-containing monooxygenase, metabolic intermediate complex, mechanismbased inactivation, suicide substrate Abstract:The inactivation of cytochrome P450 enzymes by cyclopropylamines has been attributed to a mechanism involving initial one-electron oxidation at nitrogen followed by scission of the cyclopropane ring leading to covalent modification of the enzyme. Herein we report that in liver microsomes Ncyclopropylbenzylamine (1) and related compounds inactivate P450 to a large extent via formation of metabolic intermediate complexes (MICs) in which a nitroso metabolite coordinates tightly to the heme iron, thereby preventing turnover. MIC formation from 1 does not occur in reconstituted P450 systems with CYP2B1/2, 2C11 or 2E1, or in microsomes exposed to gentle heating to inactivate the flavincontaining monooxygenase (FMO). In contrast, N-hydroxy-N-cyclopropylbenzylamine (3) and Nbenzylhydroxylamine (4) generate MICs much faster than 1 in both reconstituted and microsomal systems. MIC formation from nitrone 5 (PhCH=N(O)cPr) is somewhat faster than from 1, but very much faster than the hydrolysis of 5 to a primary hydroxylamine. Thus the major overall route from 1 to a P450 MIC complex would appear to involve FMO oxidation to 3, further oxidation by P450 and/or FMO to nitrone 5' (C2H4C=N(O)CH2Ph), hydrolysis to 4, and P450 oxidation to α-nitrosotoluene as the precursor to oxime 2 and the major MIC from 1.

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Cytochromes P-450 in rats: structures, functions, properties and relevant human forms

Cited by 221 publications

References 154 publications

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Use of Isolated Hepatocyte Preparations for Cytochrome P450 Inhibition Studies: Comparison with Microsomes forK_iDetermination

Cyclopropylamine inactivation of cytochromes P450: Role of metabolic intermediate complexes

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Cytochromes P-450 in rats: structures, functions, properties and relevant human forms

Cited by 221 publications

References 154 publications

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Use of Isolated Hepatocyte Preparations for Cytochrome P450 Inhibition Studies: Comparison with Microsomes forKiDetermination

Cyclopropylamine inactivation of cytochromes P450: Role of metabolic intermediate complexes

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Use of Isolated Hepatocyte Preparations for Cytochrome P450 Inhibition Studies: Comparison with Microsomes forK_iDetermination