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PubMed2004

FT-IR and NMR spectroscopic studies of salicylic acid derivatives. I. Gentisamide -- a metabolite of salicylamide.

Gentisamide (GAM, 2,5-dihydroxybenzamide), a minor first-pass metabolite of salicylamide (SAM, 2-hydroxybenzamide), was studied using FT-IR, 1D and 2D homo- and heteronuclear 1H and 13C NMR spectroscopy. GAM was isolated from human urine eight hours after oral administration of SAM. FT-IR, 1H and 13C NMR spectra unequivocally confirmed the chemical structure of GAM through chemical and substituent shifts, coupling constants and connectivities in COSY, NOESY, HETCOR and HBMC spectra. From NOESY spectra of GAM in DMSO-d6, it was concluded that the amide protons are oriented toward the ortho-proton at C-6. Obtained results indicate that the presence of the additional phenol group at C-5 in GAM favours the formation of intramolecular hydrogen bonding of the O...HO type between C2-OH proton and oxygen atom of the amide group.

Benzamides↗
PubMed1990

Sequential metabolism of salicylamide exclusively to gentisamide 5-glucuronide and not gentisamide sulfate conjugates in single-pass in situ perfused rat liver.

Gentisamide (GAM), the hydroxylated metabolite of salicylamide (SAM), underwent sequential metabolism, and GAM-5-glucuronide was the only metabolite detected in the single-pass in situ rat liver preparation (10 ml/min/liver) perfused at varying SAM steady-state input concentrations (CIn). The exclusive formation of GAM-5-glucuronide was unexpected, because GAM, when administered to the rat liver, formed predominantly monosulfate conjugates at the 5- and 2-positions (Morris et al., J. Pharmacol. Exp. Ther. 245: 614-624, 1988). Kinetic parameters obtained from single-pass studies for SAM sulfation (CIn increasing from 31 to 347 microM) and glucuronidation and hydroxylation (CIn decreasing from 1383 to 130 microM, with 0.85 mM SO4(2-), and CIn increasing from 32 to 800 microM in an absence of SO4(2-), with 2,6-dichloro-4-nitrophenol, a sulfation inhibitor) revealed sulfation as a high-affinity, high-capacity pathway, glucuronidation as a lower-affinity, high-capacity pathway and hydroxylation as a low-affinity, low-capacity pathway. However, these parameters would not explain the exclusive glucuronidation of GAM when generated from SAM. Rather the zonal localization of metabolizing activities [a periportal sulfation, evenly distributed glucuronidation, and perivenous hydroxylation system (Xu and Pang, J. Pharmacokinet. Biopharm. 17: 645-671, 1989; Morris et al., J. Pharmacokinet. Biopharm. 16: 633-656, 1988)] could explain the complete lack of sulfation in SAM sequential metabolism. The different metabolite patterns arising from the administrations of a metabolite precursor (SAM) versus a preformed metabolite (GAM), due to the proximity of enzymes for formation and sequential metabolism, may serve to explain the differential toxic or pharmacologic effects observed in other precursor-metabolite pairs.

Animals↗
PubMed1990

Effect of UDP-glucuronic acid depletion by salicylamide on biliary bilirubin excretion in the rat.

To determine the effect of UDP-glucuronic acid (UDPGA) depletion on bilirubin metabolism, salicylamide (SAM, which is metabolized primarily through glucuronidation, was administered to rats at a dose of 2 mmol/kg, and biliary bilirubin excretion and the proportion of bilirubin glucuronides were determined. At 15 min after administration of SAM, the UDPGA level in the liver was markedly decreased. Although the total biliary excretion of bilirubin showed no change, the bilirubin diglucuronide level in the 0- to 30-min period after SAM administration was significantly lower (36.9 +/- 4.3%) than that of the untreated control group during the same period (47.5 +/- 1.7%; P less than .01). The biliary bilirubin monoglucuronide (BMG) level in the 0- to 30-min period was significantly increased, compared with the control group. The C8-BMG/C12-BMG ratio in the 0- to 30-min period was significantly higher than that of the control group. At 150 min after SAM administration, there was an increase in the UDPGA level in the liver accompanied by an increase in bilirubin diglucuronide and a decrease in BMG. These results indicate that changes in UDPGA in the liver due to SAM administration influence the bilirubin composition of the bile.

Animals↗
PubMedDate not supplied

First-pass metabolism of salicylamide. Studies in the once-through vascularly perfused rat intestine-liver preparation.

Salicylamide (SAM) metabolism was studied in a once-through in situ perfused rat intestine-liver preparation in a manner which mimicked the first-pass effect. SAM (40 or 200 microM) was delivered into the intestine via the superior mesenteric artery at a flow rate of 7.5 ml/min. The intestine venous outflow into the portal vein and the hepatic arterial flow (2.5 ml/min; without drug) served as dual inflows into the liver. The steady state intestinal and hepatic extraction ratios were 0.262 +/- 0.055 and 0.992 +/- 0.014, respectively, at 40 microM, and 0.206 +/- 0.035 and 0.638 +/- 0.117, respectively, at 200 microM. SAM glucuronide was found to be the only metabolite formed by the intestine at both doses. Less than 3% of the dose was secreted into the intestinal lumen, with SAM glucuronide and SAM as the major and minor components, respectively. Hepatic metabolism of SAM, however, revealed SAM sulfation as the predominant pathway, while glucuronidation and hydroxylation were minor metabolic pathways. About 6% of the dose was excreted into bile, mostly as SAM and gentisamide glucuronides. The interrelationship between the intestine and liver clearances was also examined by mass balance considerations and simulation of data. The total rate of elimination of substrate across the two organs is the sum of the rates of metabolism by each organ. However, the overall effective extraction ratio and, hence, the clearance, are less than the sum of the individual extraction ratios and organ clearances, respectively. Our results showed that intestinal metabolism regulated the available substrate for hepatic elimination, and hence modified the contribution of hepatic metabolism in the overall first-pass effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Nonlinear intestinal first-pass metabolism of salicylamide in dogs after portacaval transposition.

The dose-dependent first-pass metabolism and pharmacokinetics of salicylamide (SAM) were studied at four dose levels in dogs before and after portacaval transposition. Four minutes after each p.o. dose, a tracer dose of [14C]SAM was given i.v. to determine clearance and bioavailability. Over the dosage range studied pretransposition, 5 to 40 mg/kg, bioavailability increased from 0.24 +/- 0.14 (mean +/- S.D.) to 0.76 +/- 0.20 (P less than .05). Clearance decreased from 3.4 +/- 1.0 to 0.6 +/- 0.11 liter/min (P less than .01) and half-life increased from 5.0 +/- 1.2 to 23.5 +/- 6.1 min (P less than .01). Over the dosage range studied post-transposition, 1.5 to 20 mg/kg, bioavailability increased from 0.31 +/- 0.09 to 0.99 +/- 0.08. Clearance and half-life had the same values and showed the same dose-dependence as in the normal dogs. The amount of SAM removed by the intestine during first-pass remained constant at about 1 mg/kg over the dose range given to the post-transposition animals. Therefore, although more easily saturable than the liver, the intestine plays an important role in first-pass metabolism of low p.o. doses of SAM. In contrast to previous results in the normal dog, the p.o. coadministration of sodium sulfate did not reduce the bioavailability of SAM in transposed dogs. This indicates that the nonlinear intestinal first-pass metabolism of SAM is not due to the depletion of the cosubstrate precursor, inorganic sulfate.

Administration, Oral↗
PubMed1986

Extrahepatic extraction of salicylamide in dogs.

Extrahepatic conjugation may be an important mechanism for the metabolism of many phenolic compounds. We have observed dose-dependent sulfoconjugation of salicylamide (SAM) in the lung, kidney and forelimb of dogs during steady-state infusions. The lungs alone accounted for more than one-half the total elimination at the lowest infusion rate (0.3 microgram/min/kg). The limbs appeared to play an important secondary role in SAM elimination whereas the kidneys made only a minor contribution to total elimination. At the highest infusion rate (500 micrograms/min/kg), extrahepatic extraction approached zero and elimination by the three extrahepatic sites fell to less than 31% of total elimination. Dose-dependent elimination at the three extrahepatic sites was responsible for most of the dose dependence observed in these studies. Extrahepatic extraction was insensitive to plasma inorganic sulfate. Clearance significantly, but only slightly, increased on coinfusing sodium sulfate at a rate that increased plasma inorganic sulfate from one-sixth (after depletion by SAM infusion) to two times normal.

Animals↗
PubMed1985

Dose-dependent sulfoconjugation of salicylamide in dogs: effect of sulfate depletion or administration.

The effects of plasma inorganic sulfate concentrations on the dose-dependent kinetics of salicylamide (SAM) were examined in the dog. Decreasing plasma sulfate concentrations from 0.9 mM to less than 0.3 mM significantly decreased clearance of a small dose of SAM (5 mg/kg) to the sulfate conjugate. Infusing sodium sulfate to prevent the decrease in plasma inorganic sulfate concentration that follows a p.o. 20-mg/kg dose of SAM did not increase SAM elimination. However, sodium sulfate given p.o. decreased SAM bioavailability, which suggests a local effect of sulfate on intestinal first-pass metabolism of SAM. These data show some dependence of SAM metabolism on plasma inorganic sulfate concentrations, but only when they are markedly reduced.

Animals↗
PubMedDate not supplied

Spectrophotometric analysis of mixtures of acetaminophen, salicylamide, and codeine phosphate in tablets.

A simple and accurate spectrophotometric procedure for the analysis of a mixture of acetaminophen, salicylamide, and codeine phosphate is described. Determination of the first 2 components depends on pH-induced differential spectral changes of their nitroso derivatives. The third component is assayed by the acid dye method. The proposed procedure was successfully applied to the analysis of laboratory-made and commercial tablets containing the ternary drug mixture.

Acetaminophen↗
PubMed1985

Effect of certain additives on the diffusion characteristics through a cellophane membrane of acetylsalicylic acid, salicylamide and phenacetin. Part 1: Effect of certain surface active agents.

The diffusion rate (D. R.) of certain ionic and non-ionic surfactant concentrations through a standard cellophane membrane was studied. D. R. of acetylsalicylic acid significantly increased in the presence of 0.1% w/v Brij 35, Tween 20 or 40 respectively. The other tested surfactants slightly increased D. R. of acetylsalicylic acid, while that of salicylamide increased in presence of 0.1% w/v of either Tween 20, 40, 60 or 80; Myrj 52 or 59; Brij 58; benzalkonium chloride, cetrimide or sodium lauryl sulphate. The highest D. R. of phenacetin was observed in presence of either 0.01% w/v Tween 20 or 0.001% w/v Brij 35.

Analgesics↗
PubMed1984

Dose-dependent bioavailability and metabolism of salicylamide in dogs.

The dose-dependent first-pass metabolism and pharmacokinetics of salicylamide (SAM) were studied at four dose levels in six dogs. Four minutes after each oral dose, a tracer dose of [14C]SAM was given i.v. to determine clearance and bioavailability. Over the dosage range studied, 5 to 40 mg/kg, bioavailability increased from 0.24 +/- 0.14 (mean +/- S.D.) to 0.76 +/- 0.20 (P less than .05). Clearance decreased from 3.4 +/- 1.0 to 0.60 +/- 0.11 liters/min (P less than .01) and half-life increased from 5.0 +/- 1.2 to 23.5 +/- 6.1 min (P less than .01). Measurement of SAM clearance to individual metabolites indicated that the sulfoconjugation and not the glucuronidation pathway was responsible for the dose-dependent effects observed. These effects occurred even at doses not expected to have caused significant depletion of body stores of inorganic sulfate; the plasma concentration of inorganic sulfate decreased by only a maximum of 13 and 26% after the 5- and 10-mg/kg SAM doses, respectively. When [14C]SAM was given alone in tracer amounts, clearance values greatly exceeded cardiac output. This suggests that SAM undergoes sulfation in organs other than the liver and intestinal wall.

Animals↗
PubMed1981

Bromination methods for determination of phenylephrine hydrochloride in nose drops, salicylamide in tablets, and tetracycline hydrochloride in capsules.

Two methods, kinetic and titrimetric, based on an electrophilic substitution reaction with bromine, are described for the assay of phenylephrine hydrochloride in nose drops, salicylamide in tablets, and tetracycline hydrochloride in capsules. The kinetic method depends on the linear relationship between concentration of the drug (microgram/mL) and time (s) for nuclear monobromination, indicated by bleaching of the methyl orange acid color. The titrimetric method is based on addition of excess of bromate-bromide with subsequent determination of excess bromine by an iodide-thiosulfate procedure. This method is also used to count the number of bromine atoms necessary for the electrophilic substitution reaction. Preservatives or tablet-capsule bases do not interfere in either method. Recoveries of drugs added to laboratory-prepared samples were good. As indicated by the F-test, the methods are equally reproducible.

Bromine↗
PubMed1996

Sequestered endoplasmic reticulum space for sequential metabolism of salicylamide. Coupling of hydroxylation and glucuronidation.

The metabolic disposition of simultaneously delivered [14C]salicylamide (SAM) (100 microM) and a tracer concentration of its hydroxylated metabolite [3H]gentisamide (GAM) was studied with single-pass followed by recirculating rat liver perfusion (10 ml/min). The use of dual radiolabeling of precursor-product pairs in single-pass and recirculating perfusions allowed for characterization of the differential metabolism of preformed [3H]GAM and formed [14C]GAM, which arose in situ in the liver with [14C]SAM single-pass perfusion, and the behavior of circulating [14C]GAM, which behaved as a preformed species in recirculation. In both modes of perfusion, [14C]SAM was mainly sequentially metabolized to [14C]GAM-5-glucuronide, whereas [3H]GAM predominantly formed [3H]GAM-5-sulfate. The steady-state and time-averaged clearances of SAM were identical and approached the value of flow, yielding a high hepatic extraction ratio (E = 0.98). The apparent extraction ratio of formed GAM [E(mi) = 0.96] was greater than that of the preformed species [E(pmi) approximately 0.7]. Because the coupling of (SAM) oxidation and (GAM) glucuronidation was a plausible explanation for the observation, a novel physiological pharmacokinetic model was developed to interpret the data. In this model, the liver was divided into three zonal units, within which acinar distribution of enzymatic activities was considered, namely periportal sulfation, evenly distributed glucuronidation, and perivenous hydroxylation. Each zonal region was subdivided into extracellular, cytosolic, and endoplasmic reticulum compartments, with cytosolic (sulfotransferases) and microsomal (cytochromes P-450 and UDP-glucuronosyltransferase) enzymes being segregated intracellularly into the cytosolic compartment and endoplasmic reticulum compartment, respectively. The simulations provided a good prediction of the present experimental data as well as previously obtained data with increasing SAM concentration and retrograde flow and supported the contention that SAM oxidation and GAM glucuronidation are coupled.

Animals↗
PubMedDate not supplied

Effect of processing technique of different dosage forms on dissolution rate of caffeine and salicylamide.

The dissolution rate of caffeine (Cf) and salicylamide (SA) from the mixtures of powders, granulate and tablets, obtained by the direct compression and wet granulation methods, has been investigated. The results presented in plots show, that the dissolution process of Cf and SA follows the first-order kinetics. The kinetic equations are used for the calculation of the dissolution rate contants (K) for the compounds of different solubility. Chromatography did not give an evidence for the formation of an adduct of Cf and SA in the granulate and tablets prepared by the wet granulation method.

Caffeine↗
PubMed1985

Determination of the theophylline solubilizer salicylamide-O-acetic acid in serum and urine using high-performance liquid chromatography.

A high-performance liquid chromatographic method for the determination of the theophylline solubilizer salicylamide-O-acetic acid has been developed in the range 0.5 to 10 microg/ml for human serum and 5 to 400 microg/ml for urine. Reversed-phase ion-pair chromatography was employed with tetrabutylammonium hydrogen sulphate as counterion and 2-nitrophenylacetic acid as internal standard. Preliminary pharmacokinetic single-dose studies show that the sensitivity and the selectivity of the assay are adequate to measure lower concentrations in the late beta-phase.

Journal Article↗