Pharmacokinetics of nitroglycerin and its metabolites after administration of sustained‐release tablets

Kwon, Hae-Ryun; Green, Preston; Curry, Stephen H.

doi:10.1002/bdd.2510130208

Cited by 13 publications

(4 citation statements)

References 8 publications

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“…In 1969; Needleman, 1975) and later confirmed by others (see w) had no effect on Ahlner et al, 1991 for review), oral GTN is completely presence of the diremoved by first pass metabolism leading to the formation of GDN metabolites. Following oral administration of GTN in doses giving prolonged (6-8 h) pharmacological effects, no plasma levels of GTN could be found (Nyberg & Westling, 1981; Kwon et al, 1992). However, under these circumstances, the plasma levels of its metabolites were of the same c nitrates such as order of magnitude as those which, when given intranversion to NO in venously, depressed blood pressure and increased pulse rate al., 1981; Murad, (Lau et al, 1991;.…”

Section: Discussionmentioning

confidence: 99%

“…Biotransformation of GTN in vascular smooth muscle preferentially gives rise to the 1,2-GDN but the ratio between 1,2-GDN/ 1,3-GDN varies depending upon the type of vascular smooth muscle tested (Brien et al, 1988;Slack et al, 1989;Kawamoto et al, 1990). In man, oral intake of GTN leads to two fold higher levels of 1,2-GDN as compared to 1,3-GDN, indicating that of the two metabolites, 1,2-GDN is probably the most important (Kwon et al, 1992). The concentrations at which the GDNs exerted their vasorelaxant and antiplatelet effects were 10-20 times higher than those of GTN (Salvemini et al, 1992a).…”

Section: Discussionmentioning

confidence: 99%

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Vascular and anti‐platelet actions of 1,2‐ and 1,3‐glyceryl dinitrate

Salvemini

Pistelli

Änggård

1993

British J Pharmacology

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1. The aim of this study was to investigate whether two metabolites of glyceryl trinitrate (GTN), 1,2 and 1,3-glyceryl dinitrate (1,2-GDN and 1,3-GDN) could account for the pharmacological effects of GTN. To this end the formation of nitric oxide (NO) from 1,2- and 1,3-GDN in the presence of bovine aortic smooth muscle cells (SMC) or endothelial cells (EC) was studied. The effects of various thiols on NO formation from these dinitrates was also evaluated. 2. 1,2-GDN or 1,3-GDN (10(-10)-10(-5) M) caused a dose-dependent relaxation of rabbit aortic strips denuded of endothelium and precontracted with phenylephrine. The dinitrates were less than one tenth as potent as GTN. 3. Incubation of 1,2-GDN or 1,3-GDN (75-2400 microM) with SMC for 30 min led to a concentration-dependent increase in nitrite (NO2-) formation but this increase was less than that produced from GTN. Likewise incubation of 1,2-GDN or 1,3-GDN with N-acetylcysteine (NAC), glutathione (GSH) or thiosalicylic acid (TSA) (all at 1 mM) for 30 min at 37 degrees C produced a concentration-dependent increase in NO2- formation. 4. Platelet aggregation induced by thrombin (40 mu ml-1) was not modified by high concentrations of 1,2-GDN or 1,3-GDN (175-700 microM). However, aggregation was inhibited when platelets were exposed to 1,2-GDN or 1,3-GDN (700 microM) in the presence of SMC (0.24-1.92 x 10(5) cells) or EC (0.8-3.2 x 10(5) cells). These effects were abrogated by co-incubation with oxyhaemoglobin (OxyHb, 10 microM) indicating that they were due to NO release. The concentrations of the dinitrates required to inhibit platelet aggregation by 50% were about 15 times higher than for GTN in the presence of the same numbers of SMC or EC.5. When NAC or TSA (both at 0.5 mM) were co-incubated with platelets for 3 min in the presence of1,2-GDN or 1,3-GDN, a concentration-dependent inhibition of platelet aggregation was observed. These anti-platelet effects were abolished by co-incubation with OxyHb (10 microM). Glutathione had no potentiating effects.6. Thus the dinitrate metabolites of GTN are metabolized to NO by SMC or EC and are acted upon by thiols to form NO at concentrations about 10 times higher than those of GTN. In vivo, after oral or intravenous GTN, GDN levels are reached which are more than 10 times higher than those of GTN.These data support the notion that part of the effects of GTN are due to the generation of NO from 1,2-GDN and 1,3-GDN by the cells of the vascular wall.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Vascular and anti‐platelet actions of 1,2‐ and 1,3‐glyceryl dinitrate

Salvemini

Pistelli

Änggård

1993

British J Pharmacology

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“…Nitroglycerin (glyceryltrinitrate,G TN, CAS 55-63-0)h as been used in the treatmentof anginapectorisformore thanac entury [1].Following oraladministration,G TN ismetabolized asafirst step totwog lyceryld initrate metabolitesbyanonspecificenzymaticprocess [2], thus forthe pharmacokineticstudyof oralGTN, its main two stable metabolites(half-lives:30 -60 min);1,2-dinitroglycerin (1,2-GDN, CAS 621-65-8) and 1,3-dinitroglycerin (1,3-GDN, CAS 623-87-0)should bed etermined in plasma [ 3].Thesetwom etabolitesexert pharmacologicale ffects qualitativelyt he same ast hoseo fthe parent drug [4].GTN isalsorapidlybroken downat3 7°Cin humanblood witht 1/2 of 6.2min [5].Asingle orald ose of 13mg nitroglycerin hasbeen administered tohealthy volunteers without anynotable side effect [6].Miyayama etal. quantified GTN and its activem etabolites in cell culturem ediumusing aliquid chromatographic-mass spectrometricmethod [7].Blumenthal etal.…”

Section: Introductionmentioning

confidence: 99%

Determination of glyceryl trinitrate and its two main metabolites in human plasma using a new sensitive gas chromatography method

Ghandforoush-Sattari

Zakeri–Milani

Mashayekhi³

et al. 2011

Arzneimittelforschung

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The aim of the present study was to determine the concentrations of nitroglycerin (glyceryl trinitrate, GTN, CAS 55-63-0) and its two main stable metabolites; 1,2-dinitroglycerin (1,2-glyceryl dinitrate, GDN, CAS 621-65-8) and 1,3-dinitroglycerin (1,3-GDN, CAS 623-87-0) in human plasma using a capillary gas chromatography method with an electron capture detection. Using the GC conditions, linear calibrations were obtained for 1,3-GDN from 0.14 to 3 ng/mL, for 1,2-GDN from 0.06 to 6 ng/mL, and for GTN from 0.01 to 0.3 ng/mL in plasma samples by the following calibration curve equations: [y = 0.1924x - 0.0088 (r = 0.999)], [y = 0.2273x + 0.0164 (r = 0.995)], [y = 17.434x - 0.0751] for 1,3-GDN, 1,2-GDN, and GTN respectively. The calculated limits of quantification values for GTN, 1,2-GDN, and 1,3-GDN were 0.03 ng/mL, 0.2 ng/mL, and 0.15 ng/mL respectively. This method was verified with a bioequivalence study of an Iranian brand of oral sustained release nitroglycerin with an innovator formulation.

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“…According to the first approach, actual BE studies are being analyzed aiming to give evidence for the relative performance of the parent drug and the metabolite (12)(13)(14)(15)(16)(17)(18)(19)(20). A drawback of this method arises from the fact that the true condition is always unknown i.e., whether the two drug products are truly bioequivalent or not.…”

Section: Introductionmentioning

confidence: 99%

Examining the Role of Metabolites in Bioequivalence Assessment

Karalis

Macheras

2010

J Pharm Pharm Sci

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-Purpsoe. Investigate the role of metabolites in bioequivalence (BE) assessment. Methods. Sets of ordinary differential equations are used to generate concentration -time data for both parent drug (P) and metabolite (M). The calculations include 24 subjects, two different formulations (Test, Reference), and a range of Test/Reference ratios for the fraction of dose absorbed and the rate of absorption. A summarized view of these results is made through the construction of three dimensional power curves. The criteria for the choice of the preferred analyte (P or M) are based on a sensitivity analysis of the bioequivalence measure (AUC, C max ). The latter depends on the relative ability of P and M to reflect better the changes of the pharmacokinetic parameters and variability. Results. The different sensitivity properties of P and M were reflected on the power curves. For AUC, the performance of metabolite is very similar to that of the parent drug for all scenarios and models examined. A more complex behaviour is evident for C max . In most of these cases, metabolite data show higher permissiveness in the percentages of acceptance. This attribute is more evident when P exhibits high elimination rate and/or the formation of M occurs rapidly. When the Test and Reference products have similar absorption profiles, metabolite data are preferable for the determination of bioequivalence. Parent drug has the advantage for detecting better the differences in the absorption rate of two drugs. The latter is counterbalanced by the increased sensitivity of P data to the variability of the data. Conclusions. Both parent drug and metabolite share the same ability to declare BE when AUC is used as a bioequivalence measure. In case of C max , metabolite data exhibit better performance when the T and R products are truly bioequivalent or the two formulations differ in their extent of absorption. For the pharmacokinetic scenarios studied, parent drug data were found to be more sensitive to detect differences in the rate of absorption. However, in such cases, their information is much influenced by the increased variability. _______________________________________________________________________________________

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Pharmacokinetics of nitroglycerin and its metabolites after administration of sustained‐release tablets

Cited by 13 publications

References 8 publications

Vascular and anti‐platelet actions of 1,2‐ and 1,3‐glyceryl dinitrate

Vascular and anti‐platelet actions of 1,2‐ and 1,3‐glyceryl dinitrate

Determination of glyceryl trinitrate and its two main metabolites in human plasma using a new sensitive gas chromatography method

Examining the Role of Metabolites in Bioequivalence Assessment

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