Pharmacokinetics of graded oral doses of sulindac in man

Pharmacokinetics of graded doses of sulindac were studied on 9 healthy volunteers. Serum concentrations of sulindac (inactive prodrug), sulindac sulfide (active metabolite) and sulindac sulfone (inactive metabolite) were measured both after a single dose of 150 mg, 175 mg or 200 mg and on the 6th and 7th days after b.i.d. administration of the same doses. The peak and minimum concentrations of sulindac were practically not dependent on the dose. The concentration-time curves remained similar after a single dose and after the repetitive dosing. On the contrary, both sulindac sulfide and sulfone gave about twice as high serum levels at steady-state as after a single dose. As judged from several pharmacokinetic parameters, a dose of 150 mg gave significantly smaller values than the higher doses but there was no significant difference between 175 mg and 200 mg in sulindac sulfide and sulfone concentrations. The average half-lives of sulindac, sulindac sulfide and sulfone were 1.7 -4.2 h, 15.3-16.1 h and 16.6-19.6 h, respectively. Both sulindac sulfide and sulfone tended to accumulate at a repetitive dose of 200 mg. The appropriate dose of sulindac appears to be 175 mg twice daily.     

Repeated dose pharmacokinetics of pancopride in human volunteers

The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL^?1. The maximum plasma concentration (mean ± SD) after the first dose was 92.5 ± 41.5 ng mL^?1 and t_max was 1.7 ± 0.9 h. The elimination half-life (t_1/2) was 14.3 ± 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 ± 396 ng h mL^?1. The maximum plasma concentration (mean ± SD) at steady state (day 5) was 101.8 ± 36.9 ng mL^?1 and t_max was 2.2 ± 1.2 h. The elimination half-life (t_1/2) was 16.3 ± 2.7 h and the minimum plasma concentration (C) was 16.6 ± 6.9 ng mL^?1. The area under the concentration-time curve during the dosing interval (AUC) was 995 ± 389 ng h mL^?1. The average plasma concentration at steady state (C) was 43.3 ± 16.1 ng mL^?1 and the experimental accumulation ratio (R_AUC) was 1.34 ± 0.19, whereas the mean theoretical value (R) was 1.40 ± 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration. The safety parameters showed no clinically relevant alterations.     

The 14C, 13C,and 15N syntheses of a potent VEGFR‐2 kinase inhibitor,Brivanib, and its prodrug,Brivanib Alaninate

The interruption of tyrosine kinase vascular endothelial growth factor receptor‐2 (VEGFR‐2) signaling by the binding of a small molecule inhibitor, for example, Brivanib, to VEGFR‐2 kinase domain has been shown as an effective method of slowing angiogenesis and tumor progression. [¹⁴C]Brivanib, 13 and its prodrug [¹⁴C]Brivanib Alaninate, 15 were prepared to support preclinical and clinical studies. Their respective stable isotope‐labeled versions, [¹³CN₂]Brivanib, 21 and [¹³CN₂]Brivanib Alaninate, 28, were also prepared to support bioanalytical LC‐MS analyses of clinical samples. All of the four title compounds were synthetically derived from the respective isotopically labeled common pyrrolotriazinone intermediate, 6 or 16. This labeled central core pyrrolotriazinone was also conveniently used to synthesize other structurally related drug discovery candidates. Copyright © 2011 John wiley & Sons, Ltd.     

Inhibition of sulindac metabolism by dimethyl sulfoxide in the rat

Dimethyl sulfoxide (DMSO) suppresses conversion of the prodrug sulindac to its bioactive sulfide metabolite (SD) by competitively inhibiting sulfoxide reductase. During continuous iv infusions of sulindac (1 mg/kg X h), plasma concentrations of SD at steady-state equilibrium were 80% lower when DMSO was infused concomitantly at 0.34 ml/kg X h, whereas sulindac plasma concentrations were not significantly affected by DMSO. Dermal application and intragastric administration of DMSO also inhibited SD accumulation in plasma. DMSO was only a weak inhibitor of SD oxidation in vitro and did not affect the rate of SD elimination in vivo. In contrast, dimethyl sulfide, a metabolite of DMSO, was a potent inhibitor of SD oxidase in vitro. These data suggest that DMSO can inhibit bioactivation and, hence, the antiinflammatory effects of sulindac.     

Metabolism of thymoxamine. I. Studies with 14C-thymoxamine in rats

Thymoxamine is rapidly and completely absorbed in rats. It is a prodrug which does not enter the systemic circulation in its unchanged form. After either oral or intravenous administration it undergoes rapid and intense metabolism involving four biotransformation reactions: Enzymatic hydrolysis to the corresponding phenol (metabolite I), Monodemethylation to metabolite II, Sulfate conjugation of I and II (metabolites III and IV) and Conjugation of I and II with glucuronic acid (metabolites V and VI). With these 6 metabolites identified approximately 95% of the radioactivity can be accounted for in plasma, urine and bile. Whereas the systemic availability of I and II is low, III and IV show high bioavailability. Metabolites I to IV are pharmacologically active, while III and IV are less potent than I and II. The radioactivity distribution in tissues is different after oral and intravenous administration consistent with the higher portion of unconjugated metabolites in the body after administration by parenteral route. Although 60% of the labelled compounds is eliminated via bile, the radioactive compounds are almost completely excreted in the urine after both routes of administration. This demonstrates complete reabsorption of the biliary metabolites. Secondary peaks of radioactivity in plasma and organs at 4 hours are explained by the participation of the metabolites in the enterohepatic circulation.     

Influence of concentration-dependent protein binding on serum concentrations and urinary excretion of disopyramide and its metabolite following oral administration

Concentrations of disopyramide (D) and mono-N-dealkyldisopyramide (MND) were measured in serum and urine following administration of 100, 150, 200, and 300 mg D to four volunteers. The free fraction of D in serum was drug concentration-dependent in all four subjects following the administration of the four doses. Areas under the free (unbound) D serum concentration-time curves (AUC) were linearly related to dose following 100–200 mg D. AUC values were 30–60 per cent higher than expected in two subjects following 300 mg D due to an apparent dose-dependent decrease in D renal tubular secretion. Renal clearance of free D averaged 10·91h^?1. The renal clearance of MND averaged 10·31h^?1. The urinary excretion of MND was proportional to disopyramide dose.     

Pharmacokinetics of cefoxitin administered intramuscularly to rabbits with experimentally-induced renal impairment

The pharmacokinetics of Cefoxitin were studied in rabbits with normal renal function and with varying degrees of renal impairment induced experimentally by uranyl nitrate. All animals received a single intramuscular (i.m.) dose of 40 mg kg^?1 of the antibiotic. The concentrations of Cefoxitin were determined in plasma, urine, and bile by a microbiologic plate diffusion method. The antibiotic follows a two-compartment open kinetic model. In rabbits with renal impairment there is a decrease in α, β K₁₂, K₁₂, K_a and an increase in V_d and the (AUC) with respect to the values obtained for rabbits with normal renal function. Linear relationships are established between log β and logK₁₃ and the serum creatinine. Biliary excretion of Cefoxitin is increased in states of renal impairment. A linear relationship is established between the percentage of the dose excreted in bile and the serum creatinine.     

Metabolism of BW 1370U87 in rat,dog, and man

BW 1370U87 is a potent, selective inhibitor of rat and human brain MAO-A. The plasma concentrations of BW 1370U87 and its metabolites were determined in rat, dog, and man. After an oral dose, BW 1370U87 undergoes extensive first-pass metabolism in all species studied. The 1-(1,2, dihydroxyethyl) metabolite, BW 1003U88, was a major metabolite in rat, dog, and human plasma. The 1-(1-hydroxyethyl) metabolite, BW 183U88, was a major metabolite in dog plasma, whereas it was present in much lower concentrations in the rat and man. Both BW 1003U88 and BW 183U88 are active MAO-A inhibitors although not as active as the parent compound. The inactive 1-(2-acetic acid) metabolite, BW 1552U88, was a major metabolite in rat plasma but a minor metabolite in the dog. Plasma concentration versus time profiles in both rat and man suggest that the metabolites undergo enterohepatic recycling. Although plasma concentrations of BW 1370U87 were relatively low compared to the metabolites, the concentrations detected in rat and man after a 50 mg/kg or 400 mg oral dose, respectively, exceeded the IC₅₀ value measured in rat and human brain. Furthermore, the time course of MAO-A inhibition appears to follow the plasma concentration versus time profile of BW 1370U87 in the rat. Preliminary experiments in rats indicate that BW 1370U87 and its metabolites distribute into brain and inhibit MAO-A.     

Effects of heavy metals on the biology of a N2-fixing cyanobacterium Anabaena doliolum

The effects of copper, nickel, and iron on survival, growth, nutrient uptake (NH, NO, and PO), carbon fixation, nitrate reductase, nitrogenase (CH₂ reduction assay), glutamine synthetase (transferase), and alkaline phophatase activities of Anabaena doliolum were studied. About 50% survival of the test alga was scored at 8.0 × 10^?3, 8.6 × 10^?3, and 0.36 mM of Cu, Ni, and Fe, respectively. However 45, 59, and 57% reductions in final yield were scored, respectively, at LD₅₀ concentrations of Cu, Ni, and Fe. On the basis of the LD₅₀ of the test metals, Ni was the most inhibitory for nutrient uptake. However, the LD₅₀ concentrations of Cu, Ni, and Fe showed different levels of inhibition for different processes. Although metal concentrations higher than LD₅₀ were found to be more inhibitory, 0.54 mM iron generated maximum inhibitory effect as compared to Cu and Ni. The present study demonstrates that the test cyanobacterium exhibits metal and dose-specific responses toward different physiological and biochemical processes.     

Effects of a new 1,3,4‐thiadiazolium mesoionic compound,MI‐D,on the acute inflammatory response

A new mesoionic compound, 4‐phenyl‐5‐(4‐nitro‐cinnamoyl)‐1,3,4‐thiadiazolium‐2‐phenylamine (MI‐D), is described along with some of its biological properties. Its effects on hepatic metabolism, on O and nitric oxide (NO) production, and in in vivo models for potential antinociceptive, antipyretic, and antiinflammatory activities were determined. In perfused rat liver, MI‐D (25 µM) stimulated glycogenolysis (95%), and inhibited oxygen uptake (37%) with affecting glycolysis. In phorbol 12‐myristate 13‐acetate‐stimulated macrophages, O generation was reduced (95%) by MI‐D (15 µM), whereas the production of NO was unaffected. MI‐D (2 mg/kg) inhibited (55%) the number of abdominal writhings induced by acetic acid. At 1 mg/kg, MI‐D inhibited the febrile response (5 h) induced by lipopolysaccharide (LPS) and was also effective against a preexisting febrile response. Treatment with MI‐D (1 mg/kg) reduced by 67% prostaglandin (PGE₂) levels in the cerebrospinal fluid of LPS‐exposed mice, and at a higher dose (8 mg/kg) MI‐D inhibited paw edema formation (2 h) induced by carrageenan. MI‐D has a spectrum of activities similar to other nonsteroidal antiinflammatory drugs, qualifying it as a potential anti‐inflammatory drug. Drug Dev. Res. 61:207–217, 2004. © 2004 Wiley‐Liss, Inc.     

Comparative disposition of sulindac and metabolites in five species.

The disposition of the new anti-inflammatory agent,cis-5-fluoro-2-methyl-1-[p-(methylenesulfinyl)-benzylidene]-indene-3-acetic acid [sulindac] and its sulfide and sulfone metabolites was studied in five laboratory species. In each, oxidative biotransformation of the parent sulfoxide (sulindac) to sulfone is irreversible, while reduction to sulfide is reversible. The areas under the plasma concentration curves [AUC] of each redox form vary within each species as a function of the form which is administered and, because of differences in the reversible biotransformations and in enterohepatic circulation, vary widely among species for any given redox form administered. Corresponding variations in anti-inflammatory responses, within species, is a monotonic function of the AUC of sulfide, but not of that for sulfoxide or sulfone. A similar correlation is apparent between intestinal toxicity, to the extent that it occurs, and cumulative biliary secretion of the sulfide. Thus, additional evidence is provided for the putative role of the sulfide metabolite as the biologically active form of sulindac.     

Stabile Pyridophenanthridiniumsalze mit Acyliminium-Partialstruktur, 1. Mitt

Stable Pyridophenanthridinium-Salts with Acyliminium Partial Structure, 1. Comm Stable crystalline acyliminiumfluoroborates 7a – c·BF₄ ^? are synthesized from tetracyclic lactams 6a – c by NOBF-dehydrogenation. Treatment of 6b , c with bromine affords less stable bromides 7b – c·Br ^?. On reaction with NaHCO₃-solution the salts 7 are converted into carbinolamides 8 , from which the salts 7a – c·BF₄ ^? and 7a – c·Br ^? can be regenerated with BF₃·Et₂O and SOBr₂. α-Amidoalkylation reactions of the acyliminiumsalts 7 and carbinolamides 8 with O- and C-nucleophiles are described.     

The synthesis and use of [14C]carbon monoxide in Pd‐catalyzed carbonylation reactions

The [¹⁴C]carbonylation reaction is a very powerful method of incorporating C‐14 into a drug molecule late in a radiochemical synthesis. The first and perhaps most critical step in [¹⁴C]carbonylation reactions is the generation of ¹⁴CO and its subsequent delivery to the reaction flask. There are three published methods for generating ¹⁴CO: conversion of ¹⁴CO₂ with Zn at 400°C, pyrolysis of Ca¹⁴CO_3, and dehydration of NaOCH. Additionally, a newly published method for the in situ carbonylation of aryl and vinyl halides to give acids has been investigated using NaOCH as the labeled precursor. Finally, the application of ¹⁴CO in Pd‐catalyzed [¹⁴C]carbonylation reactions will be discussed. Copyright © 2010 John Wiley & Sons, Ltd.     

Mitochondrial uncoupling by the sulindac metabolite, sulindac sulfide

Sulindac is a non-steroidal antiinflammatory drug (NSAID) known to inhibit cyclooxygenases (COX) 1 and 2, and at present of interest for cancer prevention. However, its therapeutic use has been limited by its toxicity to the gastrointestinal tract and liver. We address the effects of sulindac, of the pharmacologically inactive metabolite, sulindac sulfone, and of the pharmacologically active metabolite, sudindac sulfide, on isolated rat liver mitochondria and HepG2 cells. Sulindac sulfide, but not sulindac sulfone or sulindac itself, caused mitochondrial uncoupling, released preaccumulated Ca2+ from the organelle, and decreased Hep-G2 cell viability in apparent association with cell ATP depletion resulting from mitochondrial uncoupling-associated membrane potential dissipation.     

The effects of sulindac and its metabolites on acute stress-induced gastric ulcers in rats

Rats were given a single intragastric administration of the prodrug sulindac (4.0 mg/kg) or its sulfide (1.0, 2.0, 4.0, or 8.0 mg/kg) or sulfone (1.0, 2.0, 4.0, or 8.0 mg/kg) metabolites and were then subjected to acute stress in the form of immobilization for 3 hr in a cold environment. Control rats received an equal volume of propylene glycol vehicle or nothing po. Other rats received 200 mg/kg acetylsalicylic acid (ASA) with or without stress, to compare the gastrointestinal effects of sulindac metabolites with those of a known non-steroidal anti-inflammatory agent. The sulfide metabolite exacerbated stress-induced gastric glandular ulcer incidence and severity in a dose-related manner relative to all groups except the ASA-stress group, which exhibited the greatest amount of gastric damage. The sulfone metabolite did not potentiate ulcer incidence or severity beyond control (stress only) levels at lower doses. However, at 4.0 and 8.0 mg/kg, the observed ulceration was greater than that seen in stressed but otherwise untreated animals. Sulindac, vehicle, and otherwise untreated rats exhibited a similar degree of stress-induced gastric damage. It appears that the prodrug does not significantly enhance stress-related gut disease, but that the active sulfide metabolite does. Although the clinical literature suggests that the sulfone metabolite is inactive, the present results suggest otherwise. While this metabolite did not, by itself, induce gastric damage at higher doses, sulfone did exacerbate stress ulcer formation. This is the only report of which we are aware, indicating a possible toxic effect of the sulfone metabolite.     

Interaction of sulindac and metabolite with human serum albumin

The binding of the newly developed nonsteroidal anti-inflammatory agent sulindac and its principal active metabolite, sunlindac sulfide, to human serum albumin was investigated. With the methods of dialysis, fluorescence quenching, and difference spectrophotometry, it was found that both agents were extensively bound to albumin. The binding affinity of the metabolite was considerably higher than that of sunlindac and this effect may be related to its prolonged plasma half-life versus the parent drug. Sulindac binding was albumin concentration dependent, which gave rise to an unfamilar Scatchard analysis of the dialysis data.     

Dose-dependent kinetics of all-trams-retinoic acid in rats: Plasma levels and excretion into bile,urine, and faeces

Plasma concentration-time curves for all-trans-retinoic acid (RA) after 0.015.0.25 or 5 mg/kg, i.V., deviated from first-order kinetics in the rat. Within 10 min after the i.v. infusion, a rapid, dose-dependent decrease in RA concentration was observed (slope steepest at the lowest dose). During a secondary phase of slower decline, the times required to halve the RA concentration after 0.015, 0.25 and 5 mg/kg were 40, 65 and 120 min respectively. At later times, the concentration-time curves for all three dose levels assumed a fast rate of decline (half-life about 19 min at the lower dose). The dose-dependent kinetics of RA in plasma were not due to enterohepatic recirculation of RA, since RA levels in plasma were not lower in rats with biliary fistulas given comparable doses. In contrast, circulating levels of RA metabolites remained elevated for several hours and were significantly diminished by interruption of the enterohepatic circulation. After a dose of [10-3H]RA, the rate of biliary excretion of radiolabeled material was initially slower after 5 mg/kg RA than after 0.015 mg/kg RA. Within the first 24 hr, however, approximately the same proportion of both doses appeared in bile. All-trans-retinoyl-β-glucuronide is only a minor biliary metabolite of RA. Glucuronidation of RA was dose-dependent, since the percentage of total biliary metabolites represented by all-trans-retinoyl-β-glucuronide increased with increasing dose. Renal excretion of RA and its metabolites was significantly decreased by interruption of the enterohepatic circulation. The percentage of dose excreted in the urine decreased with increasing dose.     

A reversible clearance model for the enterohepatic circulation of drug and conjugate metabolite pair

An analytic expression for the plasma clearance of a drug, which undergoes enterohepatic circulation (EHC) in intact form and in the form of a hydrolyzable conjugate metabolite, was derived based on a four-compartment model that features the three successive steps of the recycling cascade: biliary excretion, intestinal hydrolysis, and reabsorption. The kinetic equation consists of irreversible and partially reversible clearance terms. The irreversible terms represent the removal of drug from the systemic circulation in a unidirectional fashion, such as renal clearance and extraconjugative biotransformation pathways. The reversible terms represent the two recycle pathways: biliary excretion of the parent compound, and the formation of a conjugate metabolite and its subsequent excretion into bile. Mathematically, the reversible clearance terms can be resolved into the product of a net recycled fraction and an irreversible clearance estimate for either biliary excretion or conjugate formation. The net recycled fractions are, in turn, a function of the competitive kinetics of drug or drug conjugate at each step of the EHC cascade. The derived clearance equation provides a useful conceptual framework in the kinetic analysis of factors controlling the reversibility of plasma drug clearance as a result of EHC. Analysis of the model also points to the development of new experimental strategies in elucidating the EHC of xenobiotics.     

Effect of enterohepatic circulation on the pharmacokinetics of spironolactone in man

Summary 100 Ci ³H-spironolactone together with 300 mg unlabeled drug were administered orally to 8 patients, 24 h after choledochotomy with subsequent complete drainage of bile for a further 96 h by means of a special tube. To evaluate the role of entero-hepatic circulation, the excretion of tritiated substances in bile was investigated and their kinetics in plasma and urine were compared with that of controls.The ³H-activity in plasma declined monoexponentially with t _1/2: 1.80±0.12 d from 12 h after patients received the drug. This half life was not different from that of controls in the terminal slope, 96–144 h after administration. However, between 24–96 h the elimination was significantly delayed (t _1/2: 2.79±0.29 d) in controls. This was the result of entero-hepatic cycling of spironolactone metabolites with high biliary clearance.5.4–32.7% of the dose was excreted in bile within 4 days; of this 50–70% consisted of polar material, 10–20% of canrenone, 5–15% of 6-OH-7-methylsulfinyl-spirolactone and 3–10% of 6-OH-7-thiomethyl-spirolactone. In urine, identical percentages of the dose were excreted in patients and controls. TLC-examination of the lipophilic fraction revealed less sulfoxidized metabolites while, at the same time, significantly higher amounts of 6-OH-7-thiomethylspirolactone and canrenone were eliminated in patients with biliary fistula.Thus, interruption of enterohepatic circulation had resulted in a shift of metabolic pathways of this drug in spite of an unchanged overall metabolic rate. Furthermore, the experiments allow a logical interpretation of the kinetics of ³H-activity in plasma after administration of ³H-spironolactone in normal man.This paper includes parts of the thesis of U. Hirschberger     

Effect of sulfur dioxide and particulate pollutants on bronchitis in children—A risk analysis

The general morbidity is being influenced to a great extent by diseases of the respiratory tract. Since their incidence and prevalence have been increasing, the identification of causal factors, especially of environmental origin, is of importance, not just in view of implementing preventive control strategies. Primary irritative gaseous [like sulfur dioxide (SO₂)] as well as particulate pollutants (like TSP) can be regarded as causal constituents. Using the opportunity of changing levels of ambient air pollution in East Germany since 1989, the impact of SO₂ and TSP on bronchitis was investigated over the last 10 years as part of several intervention studies in a locally defined homogenous population, children. The data suggest a significant association between SO₂ and the prevalence of bronchitis in children but not for TSP. Considering the findings of other studies with respect to air pollution and the epidemiology of adverse health effects (especially respiratory disease), these results would amend the hypothesis put forward in a review of the literature as TSP<ultrafine particles (SO)=SO₂. Although these data show a significant association with only SO₂, this does not imply that ultrafine particles, such as SO, do not contribute to the association with the observed adverse health effects. Nevertheless, the findings suggest that TSP seems less likely to be a predictor in the association with respiratory diseases, particularly not in the presence of high SO₂. © 2001 John Wiley & Sons, Inc. Environ Toxicol 16: 269–276, 2001