Cytochrome P-450 mediated biotransformation of organic nitrates

1990 ◽  
Vol 68 (12) ◽  
pp. 1552-1557 ◽  
Author(s):  
Bernard J. McDonald ◽  
Brian M. Bennett
Keyword(s):  
Glyceryl Trinitrate ◽  
Microsomal Fraction ◽  
Direct Interaction ◽  
Organic Nitrate ◽  
Organic Nitrates ◽  
Aerobic Conditions ◽  
First Order ◽  
Preferential Formation ◽  
First Order Kinetics ◽  
Cytochrome P 450

The vascular biotransformation of organic nitrates appears to be a prerequisite for their action as vasodilators. In the current study, we assessed the involvement of cytochrome P-450 in the denitration of glyceryl trinitrate and the enantiomers of isoidide dinitrate. Denitration of organic nitrates by the microsomal fraction of rat liver was NADPH dependent and followed apparent first-order kinetics. Under aerobic conditions, the t1/2 of D-isoidide dinitrate was significantly shorter than that of L-isoidide dinitrate (11.9 vs. 14.1 min, p ≤ 0.05), which is consistent with the greater potency of the D-enantiomer for vasodilation. Under anaerobic conditions, the denitration of glyceryl trinitrate was very rapid (t1/2 approximately 30 s). Organic nitrate biotransformation was inhibited by carbon monoxide, SKF 525A, and dioxygen. This suggests that the biotransformation of organic nitrates can occur through the direct interaction with the heme moiety of cytochrome P-450. The biotransformation of glyceryl trinitrate was catalyzed preferentially by those isoenzymes induced by phenobarbital. The biotransformation of glyceryl trinitrate was regioselective for 1,3-glyceryl dinitrate formation except in phenobarbital-induced microsomes under aerobic conditions, in which preferential formation of 1,2-glyceryl dinitrate occurred. These data suggest that cytochrome P-450 is involved in the biotransformation of organic nitrates and raises the possibility that vascular cytochrome P-450 may play a role in the mechanism-based biotransformation of organic nitrates, the result of which is vascular smooth muscle relaxation.Key words: cytochrome P-450, glyceryl trinitrate, isoidide dinitrate, biotransformation, liver.

Inhibition of nitrovasodilator- and acetylcholine-induced relaxation and cyclic GMP accumulation by the cytochrome P-450 substrate, 7-ethoxyresorufin

1992 ◽  
Vol 70 (9) ◽  
pp. 1297-1303 ◽  
Author(s):  
Brian M. Bennett ◽  
Bernard J. McDonald ◽  
Rita Nigam ◽  
Patrick G. Long ◽  
W. Craig Simon
Keyword(s):  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Cyclic Gmp ◽  
Guanylyl Cyclase ◽  
Competitive Inhibition ◽  
Direct Interaction ◽  
Inhibitory Effect ◽  
Rat Aorta ◽  
Endothelial Nitric Oxide ◽  
Cytochrome P 450

We examined the effect of the cytochrome P-450 substrate, 7-ethoxyresorufin (7-ER), and its corresponding product, resorufin, on nitrovasodilator- and endothelium-dependent relaxation of isolated rat aorta. The EC50 value for glyceryl trinitrate (GTN) induced relaxation was increased over 100-fold by 7-ER and less than 3-fold by resorufin. The EC50 value for sodium nitroprusside (SNP) induced relaxation was increased approximately 12-fold by 7-ER, acetylcholine (ACh) induced relaxation was abolished, and relaxation induced by isopropylnorepinephrine was not significantly affected. GTN-, SNP-, and ACh-induced increases in cyclic GMP accumulation were inhibited by 7-ER, as were basal cyclic GMP levels in endothelium-intact, but not endothelium-denuded tissues. 7-ER decreased GTN biotransformation in intact aorta and decreased the regioselective formation of glyceryl-1,2-dinitrate. The activation by GTN and SNP of aortic guanylyl cyclase in broken cell preparations was not affected by 7-ER, indicating that the inhibitory effect of 7-ER is probably not due to a direct interaction with guanylyl cyclase. The inhibitory effect of 7-ER on GTN-induced relaxation was not altered by the addition of superoxide dismutase, suggesting that 7-ER does not act by increasing superoxide anion concentration (which would serve to increase the degradation of nitric oxide (NO) formed during vascular GTN biotransformation). Our data provide further evidence for the role of the cytochrome P-450 – cytochrome P-450 reductase system in the biotransformation of GTN to an activator (presumably nitric oxide) of guanylyl cyclase. The data are consistent with a mode of action of 7-ER involving either competitive inhibition of vascular cytochrome P-450 or uncoupling of vascular cytochrome P-450 reductase from cytochrome P-450. The data also suggest that the cytochrome P-450 system facilitates NO release from SNP and that 7-ER has an inhibitory effect on endothelial nitric oxide synthase.Key words: glyceryl trinitrate, nitrovasodilators, cytochrome P-450, vascular smooth muscle, 7-ethoxyresorufin, endothelium, cyclic GMP.

Kinetics and mechanism of dealkylation of coordinated isocyanide in Fe(PMe3)2(t-BuNC)3

2005 ◽  
Vol 83 (6-7) ◽  
pp. 626-633 ◽  
Author(s):  
Christine L Tennent ◽  
William D Jones
Keyword(s):  
Hydrogen Atom ◽  
Iron Complex ◽  
Kinetics And Mechanism ◽  
Zerovalent Iron ◽  
Mechanistic Studies ◽  
First Order ◽  
Tert Butyl ◽  
Preferential Formation ◽  
First Order Kinetics ◽  
Thermal Cleavage

The zerovalent iron complex Fe(PMe3)2(t-BuNC)3 undergoes thermal cleavage of the C—N bond to give Fe(PMe3)2(t-BuNC)2(H)(CN) and isobutylene. The reaction follows first order kinetics, and addition of the hydrogen-atom donor 1,4-cyclohexadiene leads to the preferential formation of isobutane rather than isobutylene. Mechanistic studies are consistent with a rate determining homolysis of the C—N bond, giving rise to tert-butyl radicals.Key words: iron, isocyanide, elimination, C—N cleavage.

Patterns of isosorbide dinitrate and glyceryl trinitrate metabolites formed by selected segments of the rabbit gastrointestinal tract

1988 ◽  
Vol 66 (2) ◽  
pp. 166-170 ◽  
Author(s):  
Glen S. Tam ◽  
Heather MacMillan ◽  
Brian M. Bennett ◽  
Gerald S. Marks ◽  
James F. Brien ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Glyceryl Trinitrate ◽  
Cross Section ◽  
Metabolic Activity ◽  
Isosorbide Dinitrate ◽  
Oral Bioavailability ◽  
Organic Nitrates ◽  
Preferential Formation ◽  
Mucosal Layer ◽  
High Clearance

Homogenates of selected segments of the rabbit gastrointestinal tract (GIT) were studied for their ability to biotransform isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) to their mono- and di-nitrate metabolites, respectively. In addition, preferential formation of certain metabolites was investigated by examination of the patterns of metabolites formed by the various homogenates. After a 30-min incubation of ISDN with GIT homogenates (pH 7.4, 37 °C), the percent disappearance of ISDN and the ratio of isosorbide-2-mononitrate (2-ISMN) to isosorbide-5-mononitrate (5-ISMN) were as follows: stomach, 32%, 0.8; duodenum, 65%, 0.1; jejunum, 59%, 0.2; ileum, 38%, 1.2; cecum, 33%, 2.7; and colon, 32%, 3.4. After a 5-min incubation of GTN with GIT homogenates, the percent disappearance of GTN and the ratio of glyceryl-1,3-dinitrate (1,3-GDN) to glyceryl-1,2-dinitrate (1,2-GDN) were as follows: duodenum, 54%, 0.65; ileum, 73%, 0.68; and colon, 61%, 0.17. Incubation of 2 × 10−7 M ISDN with mucosal and muscularis homogenates of duodenum, jejunum, and ileum resulted in significant losses of ISDN with an equimolar formation of the mononitrate metabolites. Most of the metabolic activity for ISDN resided in the mucosal layer of each section. The ratio of 2-ISMN to 5-ISMN varied in each section (stomach to colon) and cross section (mucosal versus muscularis) of the GIT. We conclude that the metabolism of ISDN and GTN by the GIT may contribute to the high clearance of these organic nitrates, and the low oral bioavailability of ISDN. Also, multiple mechanisms appear to be involved in the biotransformation of ISDN and GTN in the rabbit GIT.

YC-1 enhances the responsiveness of tolerant vascular smooth muscle to glyceryl trinitrate

2001 ◽  
Vol 79 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Deirdre A O'Reilly ◽  
Brian E McLaughlin ◽  
Gerald S Marks ◽  
James F Brien ◽  
Kanji Nakatsu
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Glyceryl Trinitrate ◽  
Metabolic Activation ◽  
Nitric Oxide Donor ◽  
Organic Nitrate ◽  
Organic Nitrates ◽  
Cardiovascular Medicine ◽  
Left Shift ◽  
Concentration Response Curve

A major limitation of the use of organic nitrates in cardiovascular medicine is the development of tolerance, which has been attributed, in part, to a decrease in their metabolic activation in the vascular smooth muscle cell. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) was shown to potentiate vascular smooth muscle responsiveness to glyceryl trinitrate (GTN), sodium nitroprusside, and the nitric oxide donor NOC 18, in organic nitrate-naïve vascular smooth muscle. We used GTN-tolerant rabbit aortic rings (RARs) to test the hypothesis that a non-vasorelaxant concentration of YC-1 enhances the ability of the prototypical organic nitrate GTN to relax vascular smooth muscle and elevate intravascular cGMP under conditions of GTN tolerance. Treatment with YC-1 (3 µM) produced a left shift of the GTN concentration-response curve and decreased the EC50 value for GTN-induced relaxation in both GTN-tolerant and non-tolerant RARs (P < 0.05). Intravascular cGMP elevation induced by GTN was enhanced in the presence of YC-1 in GTN-tolerant and non-tolerant RARs (P < 0.05). These observations indicate that YC-1, or similarly acting drugs, may be useful in overcoming the tolerance that develops during sustained GTN therapy, and that its mechanism may involve enhanced cGMP formation.Key words: glyceryl trinitrate, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), organic nitrate tolerance, cGMP, vasorelaxation.

Nitric oxide formation from glyceryl trinitrate in the developing guinea-pig hippocampus

2000 ◽  
Vol 12 (6) ◽  
pp. 245 ◽  
Author(s):  
Adrian C. Crowe ◽  
Malcolm E. Chang ◽  
Brian E. McLaughlin ◽  
James F. Brien
Keyword(s):  
Nitric Oxide ◽  
Guinea Pig ◽  
Glyceryl Trinitrate ◽  
Life Time ◽  
Organic Nitrate ◽  
Postnatal Life ◽  
No Donor ◽  
Aerobic Conditions ◽  
No Formation ◽  
Pharmacologic Effect

Glyceryl trinitrate (GTN) is classified as an organic nitrate vasodilator drug. GTN is considered to be a prodrug because it undergoes biotransformation at its site of action to form nitric oxide (NO) or a NO adduct, which produces its pharmacologic effect. The objectives of this study were to determine whether the hippocampus can biotransform GTN to NO using aerobic conditions, and whether biotransformation of GTN to NO is age-dependent during postnatal life. Time-dependent formation of NO occurred during the incubation of 100 µM GTN with 2.5% (w/v) homogenate of guinea-pig hippocampus at 37°C using aerobic conditions. GTN-derived NO formation was similar in magnitude for the three selected postnatal ages that were studied, that is, postnatal days 10, 20 and > 60. The data demonstrate that the capacity of the hippocampus for NO formation from GTN is fully developed in the guinea-pig in early postnatal life. In view of these findings, it is conceivable that a NO donor drug, selectively metabolized to NO in the hippocampus, could be a useful therapeutic intervention to mitigate structural and/or functional defects in this brain region resulting from decreased NO formation or availability.

Biotransformation of glyceryl trinitrate and isosorbide dinitrate in vascular smooth muscle made tolerant to organic nitrates

1989 ◽  
Vol 67 (11) ◽  
pp. 1381-1385 ◽  
Author(s):  
Christopher J. Slack ◽  
Brian E. McLaughlin ◽  
James F. Brien ◽  
Gerald S. Marks ◽  
Kanji Nakatsu
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Glyceryl Trinitrate ◽  
Isosorbide Dinitrate ◽  
Isosorbide Mononitrate ◽  
Organic Nitrate ◽  
Organic Nitrates ◽  
Nitrate Anion ◽  
Pharmacologically Active

It has been proposed that organic nitrates are prodrugs and biotransformation to a pharmacologically active metabolite (i.e., nitric oxide) must occur before the onset of vasodilation. If this postulated mechanism is correct, tolerance to organic nitrate-induced vasodilation might involve decreased biotransformation of organic nitrates by vascular smooth muscle. In this study, biotransformation of isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) was estimated by measuring isosorbide mononitrate (ISMN) and glyceryl dinitrate (GDN), respectively, rather than the nitrate anion, because of a more sensitive method for measurement of ISMN and GDN. To test this hypothesis, isolated rabbit aortic strips (RAS) were made tolerant in vitro by incubation with 500 μM GTN or ISDN for 1 h. After a washout period and submaximal contraction with phenylephrine, the tissues were incubated with either 2.0 μM [14C]ISDN or 0.5 μM [14C]GTN for 2 min. ISDN- or GTN-induced relaxation of RAS was monitored and tissue parent drug and metabolite contents were determined by thin-layer chromatography and liquid scintillation spectrometry. ISDN- and GTN-induced relaxation of RAS and the metabolite concentrations were significantly less for both GTN- and ISDN-tolerant tissue compared with nontolerant tissue. These results are consistent with the hypothesis that organic nitrate biotransformation is required for organic nitrate-induced vasodilation.Key words: organic nitrates, glyceryl trinitrate, isosorbide dinitrate, biotransformation, prodrug, tolerance.

Photo-catalytic degradation of gaseous pollutants in paper mills of southern China

TAPPI Journal ◽  
2018 ◽  
Vol 17 (03) ◽  
pp. 167-178 ◽  
Author(s):  
Xin Tong ◽  
Jiao Li ◽  
Jun Ma ◽  
Xiaoquan Chen ◽  
Wenhao Shen
Keyword(s):  
Degradation Rate ◽  
Southern China ◽  
Catalytic Degradation ◽  
Pulp And Paper ◽  
Gaseous Pollutants ◽  
Pulp And Paper Mills ◽  
Paper Mills ◽  
Initial Concentration ◽  
First Order ◽  
First Order Kinetics

Studies were undertaken to evaluate gaseous pollutants in workplace air within pulp and paper mills and to consider the effectiveness of photo-catalytic treatment of this air. Ambient air at 30 sampling sites in five pulp and paper mills of southern China were sampled and analyzed. The results revealed that formaldehyde and various benzene-based molecules were the main gaseous pollutants at these five mills. A photo-catalytic reactor system with titanium dioxide (TiO2) was developed and evaluated for degradation of formaldehyde, benzene and their mixtures. The experimental results demonstrated that both formaldehyde and benzene in their pure forms could be completely photo-catalytic degraded, though the degradation of benzene was much more difficult than that for formaldehyde. Study of the photo-catalytic degradation kinetics revealed that the degradation rate of formaldehyde increased with initial concentration fitting a first-order kinetics reaction. In contrast, the degradation rate of benzene had no relationship with initial concentration and degradation did not conform to first-order kinetics. The photo-catalytic degradation of formaldehyde-benzene mixtures indicated that formaldehyde behaved differently than when treated in its pure form. The degradation time was two times longer and the kinetics did not reflect a first-order reaction. The degradation of benzene was similar in both pure form and when mixed with formaldehyde.

Kinetic of oxidation of methyl orange by vanadium(V) under conditions VO2+ and decavanadates coexist: Catalysis by Triton X-100 micellar medium

2019 ◽  
Author(s):  
Chem Int
Keyword(s):  
Methyl Orange ◽  
Solution Ph ◽  
Vanadium Concentration ◽  
Limiting Behavior ◽  
First Order ◽  
First Order Kinetics ◽  
Ph Range ◽  
Kinetic Pattern ◽  
Triton X ◽  
Kinetics Of

The kinetics of oxidation of methyl orange by vanadium(V) {V(V)} has been investigated in the pH range 2.3-3.79. In this pH range V(V) exists both in the form of decavanadates and VO2+. The kinetic results are distinctly different from the results obtained for the same reaction in highly acidic solution (pH &lt; 1) where V(V) exists only in the form of VO2+. The reaction obeys first order kinetics with respect to methyl orange but the rate has very little dependence on total vanadium concentration. The reaction is accelerated by H+ ion but the dependence of rate on [H+] is less than that corresponding to first order dependence. The equilibrium between decavanadates and VO2+ explains the different kinetic pattern observed in this pH range. The reaction is markedly accelerated by Triton X-100 micelles. The rate-[surfactant] profile shows a limiting behavior indicative of a unimolecular pathway in the micellar pseudophase.

Biodegradation rates of aromatic contaminants in biofilm reactors

1995 ◽  
Vol 31 (1) ◽  
pp. 117-128 ◽  
Author(s):  
Jean-Pierre Arcangeli ◽  
Erik Arvin
Keyword(s):  
Aromatic Hydrocarbons ◽  
Competitive Inhibition ◽  
Removal Rate ◽  
First Order ◽  
Biofilm Reactors ◽  
First Order Kinetics ◽  
Reducing Conditions ◽  
Low Concentrations ◽  
Degradation Rates ◽  
Order Surface

This study has shown that microorganisms can adapt to degrade mixtures of aromatic pollutants at relatively high rates in the μg/l concentration range. The biodegradation rates of the following compounds were investigated in biofilm systems: aromatic hydrocarbons, phenol, methylphenols, chlorophenols, nitrophenol, chlorobenzenes and aromatic nitrogen-, sulphur- or oxygen-containing heterocyclic compounds (NSO-compounds). Furthermore, a comparison with degradation rates observed for easily degradable organics is also presented. At concentrations below 20-100 μg/l the degradation of the aromatic compounds was typically controlled by first order kinetics. The first-order surface removal rate constants were surprisingly similar, ranging from 2 to 4 m/d. It appears that NSO-compounds inhibit the degradation of aromatic hydrocarbons, even at very low concentrations of NSO-compounds. Under nitrate-reducing conditions, toluene was easily biodegraded. The xylenes and ethylbenzene were degraded cometabolically if toluene was used as a primary carbon source; their removal was influenced by competitive inhibition with toluene. These interaction phenomena are discussed in this paper and a kinetic model taking into account cometabolism and competitive inhibition is proposed.

In-vitro Kinetic Hydrolysis Study of Metronidazole Derivatives with Carvacrol and Eugenol Using Validated RP-HPLC Method

2020 ◽  
Vol 16 ◽  
Author(s):  
M. Alarjah
Keyword(s):  
Half Life ◽  
Hplc Method ◽  
Hydrolysis Rate ◽  
First Order ◽  
First Order Kinetics ◽  
Rp Hplc ◽  
Pharmacokinetic Properties ◽  
Pseudo First Order ◽  
Kinetic Hydrolysis

Background: Prodrugs principle is widely used to improve the pharmacological and pharmacokinetic properties of some active drugs. Much effort was made to develop metronidazole prodrugs to enhance antibacterial activity and or to improve pharmacokinetic properties of the molecule or to lower the adverse effects of metronidazole. Objective: In this work, the pharmacokinetic properties of some of monoterpenes and eugenol pro metronidazole molecules that were developed earlier were evaluated in-vitro. The kinetic hydrolysis rate constants and half-life time estimation of the new metronidazole derivatives were calculated using the validated RP-HPLC method. Method: Chromatographic analysis was done using Zorbbax Eclipse eXtra Dense Bonding (XDB)-C18 column of dimensions (250 mm, 4.6 mm, 5 μm), at ambient column temperature. The mobile phase was a mixture of sodium dihydrogen phosphate buffer of pH 4.5 and methanol in gradient elution, at 1ml/min flow rate. The method was fully validated according to the International Council for Harmonization (ICH) guidelines. The hydrolysis process carried out in an acidic buffer pH 1.2 and in an alkaline buffer pH 7.4 in a thermostatic bath at 37ºC. Results: The results followed pseudo-first-order kinetics. All metronidazole prodrugs were stable in the acidic pH, while they were hydrolysed in the alkaline buffer within a few hours (6-8 hr). The rate constant and half-life values were calculated, and their values were found to be 0.082- 0.117 hr-1 and 5.9- 8.5 hr., respectively. Conclusion: The developed method was accurate, sensitive, and selective for the prodrugs. For most of the prodrugs, the hydrolysis followed pseudo-first-order kinetics; the method might be utilised to conduct an in-vivo study for the metronidazole derivatives with monoterpenes and eugenol.

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