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PubMed2004

Theoretical study of gas-phase acidity, pKa, lipophilicity, and solubility of some biologically active sulfonamides.

The geometries of 19 biologically active substituted sulfonamides (including clinically useful acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) in both neutral and deprotonated forms, were optimized using Becke3LYP/6-311+G(d,p) method (compounds 1-6) and two-layered ONIOM (B3LYP 6-311+G(d,p): MNDO) method (compounds 7-19). The investigated sulfonamides are weak acids with calculated acidity of about 1320-1420 kJ mol(-1). Of acids studied the highest gas-phase acidity (1324 kJ mol(-1)) possesses methazolamide. This drug is, according to the computed pKa value (5.9), also in water solution the most acidic compound of the sulfonamides investigated. The computed pKa values varied between 5.9 and 12.6 and correlate well with the available experimental pKa's found in the literature. Cancerostatic aromatic sulfonamides 16-19 are generally weak acids with the acidity comparable or slightly lower than the lead sulfanilamide. The available experimental partition coefficients of sulfonamides investigated are best reproduced by the IA LOGP method. Computed partition coefficients for antiglaucoma sulfonamides 1-13 varied between -0.47 and 2.61 (IA LOGP). Thus these compounds are only slightly or moderate lipophilic. The lipophilicity of the cancerostatic sulfonamides 14-18 is from relatively narrow interval between -0.07 and 1.68 (IA LOGP). The most potent CAI 10-13 are also the most lipophilic compounds among the antiglaucomatics studied. The available experimental solubilities are best reproduced by the IA LOGS method. The computed solubilities qualitatively correlate with the corresponding lipophilicities, logS increasing as logP declines. The analysis of molecular descriptors defined by Lipinski have been shown that all of the sulfonamides studied obey 'Rule of 5'. Therefore, in the early stages of the design of antiglaucoma sulfonamides, it is becoming more important to determine the pKa, lipophilicity, water solubility, and other physicochemical properties associated with a drug, before synthetic work is undertaken, with the aim of avoiding the synthesis of compounds that are predicted to have poor biopharmaceutical characteristics.

Carbonic Anhydrase Inhibitors↗
PubMed2003

Generation of group-specific antibodies against sulfonamides.

To develop a sulfonamide-specific ELISA, different attempts were made to obtain monoclonal antibodies specific for the common structure of sulfonamides. In a first approach, sulfanilamide was linked to albumins using glutaraldehyde or a succinimide ester as cross-linker. A weak immune response or none at all was induced after immunization of mice with those conjugates. High antibody titers were obtained with conjugates where sulfanilamide was linked to albumins or casein (azocasein) with a diazotation reaction. However, the antibodies were only highly specific for the bound sulfanilamide molecule. In a second approach, sulfonamide-protein conjugates were used in which the sulfonamide molecule is linked at its side chain, leaving the common structure of sulfonamides unchanged. Three sulfonamide derivatives (S, TS, and PS, previously described in the literature) containing a carboxyl group in their side chain were linked to proteins using a carbodiimide mediated reaction. Immunization with the S-conjugates led to high antibody titers, but the antibodies were only highly specific for the bound S-molecule. Group-specific antibodies were obtained after immunization with the PS- and TS-conjugates. It was described that immunization with PS-conjugates lead to the recognition of other sulfonamides (sulfamethazine, -merazine, -diazine, and -dimethoxine) that are not well recognized by antibodies induced after immunization with TS-conjugates. Therefore, we tried to guide the immune response in the direction of recognition of the common structure of sulfonamides by immunizing the animals alternately with PS- and TS-conjugates. The polyclonal antibodies of the mice indeed had a broader specificity, but the specificity of the monoclonals obtained after fusion experiments was not influenced. Immunization with TS-conjugates seemed sufficient to obtain sulfonamide-specific monoclonal antibodies. With the best monoclonal (mAb 3B5B10E3) two competitive inhibition (ci) ELISA's were developed: one coated with antigen and the other coated with the monoclonal antibody. Sulfadiazine, -dimethoxine, -thiazole, -pyridine, and -methoxazole were detected in both ELISA's at their MRL-value (100 ppb) in buffer solution. Sulfadiazine, sulfathiazole, and sulfamethoxazole could even be detected at 10 ppb.

Animals↗
PubMed1999

Mechanism, structure-activity studies, and potential applications of glutathione S-transferase-catalyzed cleavage of sulfonamides.

The mechanism of sulfonamide cleavage of PNU-109112, a potent HIV-1 protease inhibitor, by glutathione-S-transferase (GST) was investigated in the presence of reduced GSH. GST-catalyzed sulfonamide cleavage takes place via the nucleophilic attack of GSH on the pyridine moiety of the substrate with formation of the GS-para-CN-pyridinyl conjugate, the corresponding amine, and sulfur dioxide. Structure activity studies with a variety of sulfonamides indicate that an electrophilic center alpha to the sulfonyl group is required for cleavage. Substituents that withdraw electron density from the carbon atom alpha- to the sulfonyl group facilitate nucleophilic attack by the GS(-) thiolate bound to GST. The rate of sulfonamide cleavage is markedly affected by the nature of the electrophilic group; replacement of para-CN by para-CF(3) on the pyridine ring of PNU-109112 confers stability against sulfonamide cleavage. On the other hand, stability of sulfonamides is less dependent on the nature of the amine moiety. These principles can be applied to the synthesis of sulfonamides, labile toward cellular GST, that may serve as prodrugs for release of bioactive amines. Tumors are particularly attractive targets for these sulfonamide prodrugs as GST expression is significantly up-regulated in many cancer cells. Another potential application could be in organic synthesis, where protection of amines as the corresponding activated sulfonamides can be reversed by GST/GSH under mild conditions.

Caco-2 Cells↗
PubMed1995

The effect of temperature on the binding of sulfonamides to carbonic anhydrase isoenzymes I, II, and IV.

We report the effect of temperature on the equilibrium dissociation constants (Kl) for a series of six sulfonamides binding to three carbonic anhydrase (CA) isoenzymes (I, II, and IV). Kl values obtained at 0 degree, 15 degrees, and 23 degrees under conditions of nearly constant and low substrate (CO2) concentration were used to calculate enthalpy and entropy changes associated with sulfonamide binding as well as to provide estimates of inhibitory potency of sulfonamides at 37 degrees. We studies four classic sulfonamide (methazolamide, benzolamide, ethoxzolamide, and sulfanilamide) and the novel sulfonamides MK-507 (dorzolamide) and CF3SO2NH2. In all cases, the Kl was observed to increase with increasing temperature, which is consistent with a negative enthalpy of sulfonamide binding. The extrapolated increase in Kl over the 0-37 degrees temperature range varied from 4-fold for sulfanilamide binding to CA l to 14-fold for CF3SO2NH2 binding to CA IV, corresponding to binding enthalpy values of -7.2 to -11.7 kcal/mol. For CA II and I, entropy changes associated with sulfonamide binding were in general modest and ranged from -5.3 to +4.1 entropy units (eu) for five of the compounds tested. In contrast, ethoxzolamide binding was associated with a relatively large positive entropy change. Also, the variatione in k(on) and k(off) with temperature were studied for three sulfonamides binding to CA II. The association rate constants for methazolamide, benzolamide, and ethoxzolamide binding showed increases of 2-fold or less, whereas dissociation constants increased 3-9-fold over the range of 0-37 degrees. Thus, the temperature effect in increasing Kl is in large part due to a faster rate of sulfonamide dissociation. Apparent activation parameters at 23 degrees for k(on) were delta H++ = -2.35 to 3.8 kcal/mol, delta G++ = 7.3 to 8.6 kcal/mol, and delta S++ = -16.2 to -32.7 entropy units. For k(off), the corresponding values were delta H++ = 5.6 to 14.5 kcal/mol, delta G++ = 19.0 kcal/mol, and delta S++ = -14.8 to -45.7 entropy units.

Carbon Dioxide↗
PubMed2003

Protease inhibitors of the sulfonamide type: anticancer, antiinflammatory, and antiviral agents.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anticarbonic anhydrase, diuretic, hypoglycemic, and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial protease inhibitory properties. Of particular interest are some metalloprotease inhibitors belonging to this class, which by inhibiting several matrix metalloproteases (MMPs) show interesting antitumor properties. Some of these compounds are currently being evaluated in clinical trials. The large number of sulfonamide MMP inhibitors ultimately reported also lead to the design of effective tumor necrosis factor-alpha converting enzyme (TACE) inhibitors, potentially useful in the treatment of inflammatory states of various types. Since both MMPs and TACE contribute synergistically to the pathophysiology of many diseases, such as arthritis, bacterial meningitis, tumor invasion; the dual inhibition of these enzymes emerged as an interesting target for the drug design of anticancer/antiinflammatory drugs, and many such sulfonamide derivatives were recently reported. Human neutrophyl elastase (HNE) inhibitors of the sulfonamide type may also be useful in the treatment of inflammatory conditions, such as emphysema, cystic fibrosis, chronic bronchitis, ischemia reperfusion injury, and acute respiratory distress syndrome. Inhibition of some cysteine proteases, such as several caspase and cathepsin isozymes, may lead to the development of pharmacological agents effective for the management of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, brain damage, and stroke. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Some clinically used HIV protease inhibitors (such as amprenavir) possess sulfonamide moieties in their molecules, which are critical for the potency of these drugs, as shown by means of X-ray crystallography, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with lower toxicity or augmented activity against viruses resistant to the such first generation drugs. Other viral proteases, such as those isolated from several types of herpes viruses may be inhibited by sulfonamide derivatives, leading thus to more effective classes of antiviral drugs.

Animals↗
PubMed1984

The binding of sulfonamides to horse liver alcohol dehydrogenase.

The binding of sulfonamides to the active site of horse liver alcohol dehydrogenase has been studied by their effect on affinity labelling and steady state kinetics. Affinity labelling with iodoacetate and BIP has been used to study binding to free enzyme. The unsubstituted sulfonamide, sulfanilamide (I), shows very weak binding compared to the other sulfonamides tested. Most important for binding is the type of substituent attached to the parent sulfonamide, particularly when as in sulfathiazole this is a heterocycle which binds to the catalytic zinc atom of the enzyme. For sulfathiazole the dissociation constant from the enzyme is pH dependent showing two pKa values. The lower at pH 7 is the pKa of the drug itself, while that at pH 9 agrees with the ionization of water bound to the catalytic zinc ion. Steady state kinetics have been carried out at pH 7.0 and 10.0 to examine sulfonamide binding to the enzyme when coenzyme is attached. Both NAD+ and NADH induce substrate competitive sulfonamide binding. Likewise sulfathiazole accelerates the dissociation of NADH from the enzyme and SO Vmax for alcohol oxidation. The latter like stimulation of the affinity labelling reaction with iodoacetate is considered to result from binding of the thiazole ring to the catalytic zinc ion. With all the sulfonamides examined hydrophobic binding and charge are important in determining affinity to the active site and the mode of binding. Sulfonamides containing pyrazole or imidazole rings can be important in alcohol therapy.

Affinity Labels↗
PubMed1989

Binding of sulfonamide and acetamide to the active-site Zn2+ in carbonic anhydrase: a theoretical study.

Self-consistent field molecular orbital (SCF MO) calculations at both 4-31G and STO-3G levels have been used to examine the binding conformations of sulfonamide and acetamide compounds to the active site of carbonic anhydrase. The results are as follows: (1) sulfonamide binds to the Zn2+ ion in its deprotonated form through the sulfonamide nitrogen to the fourth coordination site of the metal ion; (2) acetamide as neutral species binds to the basic form of the enzyme through the carbonyl oxygen to the fifth coordination site of the metal ion; and (3) the acetamidate ion binds to the acid form of the enzyme through the amide nitrogen to form a tetracoordinated metal complex with three histidine ligands. Analysis of the effects of individual active-site residues on the binding conformations of these inhibitors suggests that metal alone favors bidentate coordination of sulfonamidate and acetamidate complexes and that electron donation from three histidine ligands to the metal ion determines the formation of a tetracoordinated metal complex, which is further stabilized by the presence of Thr 199, as it receives one hydrogen bond from the sulfonamide NH- or from the acetamide NH- and donates a backbone NH hydrogen bond to a sulfonamide oxygen. The calculated binding conformation of sulfonamide and the hydrogen-bonding interactions between sulfonamide and the enzyme are consistent with the X-ray diffraction study of the AMSulf-HCA II complex. However, no X-ray structures are available for amide-HCA II complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetamides↗
PubMed2005

Cross-coupling of sulfonamide antimicrobial agents with model humic constituents.

The oxidative cross-coupling of sulfonamide antimicrobials to constituents of natural organic matter was investigated. Sulfonamide antimicrobials were incubated with surrogate humic constituents in the absence and presence of phenoloxidases (viz., peroxidase, laccase, and tyrosinase) or acid birnessite. Substituted phenols were chosen as simple model constituents to determine the structures in humic substances important for cross-coupling reactions. The extent of sulfonamide transformation was evaluated by the disappearance of the parent compound from solution. Incubation with phenoloxidases in the absence of substituted phenols resulted in little or no sulfonamide transformation. In contrast to this, direct oxidation of sulfonamides by acid birnessite was significant. Inclusion of o-diphenols and 2,6-dimethoxyphenols in reaction mixtures resulted in significant phenoloxidase-mediated transformation of sulfonamides and enhanced antimicrobial transformation in the presence of acid birnessite. Phenolic compounds with other substitution patterns were less effective in promoting sulfonamide transformation. Nuclear magnetic resonance spectroscopy experiments provided direct evidence of peroxidase-mediated covalent cross-coupling of sulfamethazine with syringic and protocatechuic acids. Our results indicate that sulfonamide antimicrobials may be chemically incorporated into humic substances. This may result in their diminished mobility, bioavailability, and biological activity.

Anti-Infective Agents↗
PubMed2003

Design of amino acid sulfonamides as transition-state analogue inhibitors of arginase.

Arginase is a binuclear manganese metalloenzyme that catalyzes the hydrolysis of L-arginine to form L-ornithine plus urea. Chiral L-amino acids bearing sulfonamide side chains have been synthesized in which the tetrahedral sulfonamide groups are designed to target bridging coordination interactions with the binuclear manganese cluster in the arginase active site. Syntheses of the amino acid sulfonamides have been accomplished by the amination of sulfonyl halide derivatives of (S)-(tert-butoxy)-[(tert-butoxycarbonyl)amino]oxoalkanoic acids. Amino acid sulfonamides with side chains comparable in length to that of L-arginine exhibit inhibition in the micromolar range, and the X-ray crystal structure of arginase I complexed with one of these inhibitors, S-(2-sulfonamidoethyl)-L-cysteine, has been determined at 2.8 A resolution. In the enzyme-inhibitor complex, the sulfonamide group displaces the metal-bridging hydroxide ion of the native enzyme and bridges the binuclear manganese cluster with an ionized NH(-) group. The binding mode of the sulfonamide inhibitor may mimic the binding of the tetrahedral intermediate and its flanking transition states in catalysis. It is notable that the ionized sulfonamide group is an excellent bridging ligand in this enzyme-inhibitor complex; accordingly, the sulfonamide functionality can be considered in the design of inhibitors targeting other binuclear metalloenzymes.

Amino Acids↗
PubMed1999

Sulfonamide resistance in clinical isolates of Campylobacter jejuni: mutational changes in the chromosomal dihydropteroate synthase.

The characterization of the genetic basis of sulfonamide resistance in Campylobacter jejuni was attempted. The resistance determinant from a sulfonamide-resistant strain of C. jejuni was cloned and was found to show 42% identity with the folP gene (which codes for dihydropteroate synthase, the target of sulfonamides) of the related bacterium Helicobacter pylori. The sequences of the areas surrounding the folP gene in C. jejuni showed similarity to those of the areas surrounding the corresponding gene in H. pylori. The folP gene of C. jejuni, which mediates the resistance, was observed to show particular features when it was compared to other known folP genes. One of these features is the presence of two pairs of direct repeats (15 and 27 bp) within the coding sequence of the gene. Comparison of the C. jejuni folP genes that mediate susceptibility and resistance revealed the occurrence of mutations that changed four amino acid residues. Resistance of C. jejuni to sulfonamides could be associated with one or several of these four mutational substitutions, which all occurred in the five different resistant isolates studied. The codon for one of these changed amino acids was found to be located in the second direct repeat within the coding sequence of the gene. The change made the repeat perfect. The transformation of both the resistance and the susceptibility variants of the gene into an Escherichia coli folP knockout mutant was found to complement the dihydropteroate synthase deficiency, confirming that the characterized sulfonamide resistance determinant codes for the C. jejuni dihydropteroate synthase enzyme. Kinetic measurements established different affinities of sulfonamide for the dihydropteroate synthase enzyme isolated from the resistant and susceptible strains. In conclusion, sulfonamide resistance in C. jejuni was shown to be associated with mutational changes in the chromosomally located gene for dihydropteroate synthase, the target of sulfonamides.

Amino Acid Sequence↗
PubMed2003

Safety of celecoxib in individuals allergic to sulfonamide: a pilot study.

OBJECTIVE: To evaluate cross reactivity between sulfonamide antimicrobials and celecoxib in patients with histories of allergies to sulfonamide antimicrobials. METHODS: Immunocompetent patients with a history of sulfonamide antimicrobial allergy who were being considered for therapy with celecoxib were prospectively enrolled. Sulfamethoxazole and trimethoprim skin prick and intradermal testing and/or an in vitro lymphocyte toxicity assay were performed. If skin testing was negative, an oral challenge with sulfamethoxazole and trimethoprim was performed. Oral challenges with celecoxib were administered to all patients. RESULTS: Twenty-eight immunocompetent patients (26 female; mean age 60 years) were evaluated. History of sulfonamide antimicrobial allergy included urticaria (n = 7), cutaneous eruptions (n = 9), and other (n = 12). Four of the 28 patients who were skin prick tested were positive to sulfamethoxazole and two of the ten patients who underwent in vitro testing were positive to sulfamethoxazole. All 28 patients were administered celecoxib and tolerated the medication. Phone call follow up in 25 patients disclosed that 15 patients continued to take celecoxib, while five patients did not take celecoxib following the oral challenge, and five discontinued celecoxib due to adverse effects, lack of drug efficacy or physician preference. CONCLUSIONS: Confusion exists regarding the potential for cross reactivity between sulfonamide antimicrobials and other sulfonamide-containing compounds. The six sulfonamide-allergic patients tolerated celecoxib uneventfully. This pilot study supports the hypothesis that the potential for cross-reactivity between celecoxib and sulfonamide antimicrobials appears to be low. However, further investigations are required to confirm this.

Administration, Oral↗
PubMed2003

Anticancer and antiviral sulfonamides.

The sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing antibacterial, anti- carbonic anhydrase, diuretic, hypoglycemic and antithyroid activity among others. A large number of structurally novel sulfonamide derivatives have ultimately been reported to show substantial antitumor activity in vitro and in vivo. Although they have a common chemical motif of aromatic/heterocyclic or amino acid sulfonamide, there are a variety of mechanisms of their antitumor action, such as carbonic anhydrase inhibition, cell cycle perturbation in the G1 phase, disruption of microtubule assembly, functional suppression of the transcriptional activator NF-Y, and angiogenesis (matrix metalloproteinase, MMP) inhibition among others. Some of these compounds selected via elaborate preclinical screenings or obtained through computer-based drug design, are currently being evaluated in clinical trials. The review summarizes recent classes of sulfonamides and related sulfonyl derivatives disclosed as effective tumor cell growth inhibitors, or for the treatment of different types of cancer. Another research line that progressed much in the last time regards different sulfonamides with remarkable antiviral activity. Thus, at least two clinically used HIV protease inhibitors possess sulfonamide moieties in their molecules, whereas a very large number of other derivatives are constantly being synthesized and evaluated in order to obtain compounds with less toxicity or activity against drug-resistant viruses. Several non nucleoside HIV reverse transcriptase or HIV integrase inhibitors containing sulfonamido groups were also reported. Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. Most compounds with antiviral activity possessing this mechanism of action incorporate in their molecules primary sulfonamide groups. Some small molecule chemokine antagonists acting as HIV entry inhibitors also possess sulfonamide functionalities in their scaffold.

Animals↗
PubMed1989

Sulfonamide residues in pork: past, present, and future.

The Food Safety and Inspection Service (FSIS) of the U. S. Department of Agriculture (USDA) has been involved for a number of years with the problem of sulfonamide residues in pork. In the 1970s, concern was raised regarding the use of sulfonamides when food safety criteria used for premarketing approval of new animal drugs and the safety data base for sulfonamides were found to be inadequate. Regulatory analytical methods for monitoring sulfonamides were developed and put to use by FSIS. With educational efforts by government and industry, by 1980 it was thought that the problem was being solved. In the 1980s, however, the sulfonamide violation rate began to increase; the USDA strengthened its educational programs, developed a rapid test for sulfonamides and pursued regulatory initiatives. By 1987 sulfonamide violations in liver tissue (i.e., greater than .1 ppm) had declined to 3.8%; however, new toxicological information associating sulfamethazine with the development of follicular cell adenomas of the thyroid gland in rats and mice led the FSIS to begin an enhanced sulfamethazine control program in the spring of 1988. The FSIS believes that production quality assurance is the key to prevention. The Agency's initiatives toward this end are designed both to encourage industry accountability and to provide disincentives for violators. The current approaches to the sulfonamide problem hold the clear promise of a satisfactory solution.

Animals↗
PubMed1998

Carbonic anhydrase inhibitors: inhibition of isozymes I, II and IV with heterocyclic mercaptans, sulfenamides, sulfonamides and their metal complexes.

A series of sulfenamides, sulfonamides and sulfonamide metal complexes have been prepared starting from 4,5-disubstituted-3-mercapto-1,2,4-triazole derivatives. The heterocyclic mercaptans were oxidized to the corresponding sulfenamides by hypochlorite in the presence of ammonia. The sulfonamides were obtained by oxidation of sulfenamides with potassium permanganate. The Zn(II) and Cu(II) complexes of the new heterocyclic sulfonamides have been prepared via the sodium salt of the ligand. Inhibition of three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV (h = human, b = bovine) with the prepared compounds has been investigated. Mercaptans were generally less inhibitory than sulfenamides, which in turn behaved as weaker inhibitors than the sulfonamides. The strongest inhibitors were the Zn(II) and Cu(II) complexes of the heterocyclic sulfonamides. Susceptibility to inhibition was generally: hCA II > bCA IV > hCA I. Although none of the obtained simple inhibitors (mercaptans, sulfenamides, sulfonamides) possessed antiglaucoma action when administered directly into the eye in experimental animals, the Zn(II) and Cu(II) complexes of some sulfonamides acted as more efficient intraocular pressure lowering agents as compared to the clinical drug dorzolamide. This constitutes an encouraging result for obtaining novel antiglaucoma drugs from this class of CA inhibitors.

Animals↗
PubMed2000

Prediction of in vivo drug-drug interactions between tolbutamide and various sulfonamides in humans based on in vitro experiments.

Drug-drug interactions between tolbutamide and sulfonamides have extensively been reported. We attempted to predict the in vivo interaction between tolbutamide and sulfonamides from the in vitro metabolic inhibition studies. The inhibition constant (K(i)) was derived from the inhibitory effects of eight sulfonamides (sulfaphenazole, sulfadiazine, sulfamethizole, sulfisoxazole, sulfamethoxazole, sulfapyridine, sulfadimethoxine, and sulfamonomethoxine) on tolbutamide metabolism. We found that the inhibitory effect of sulfaphenazole was greatest among the eight sulfonamides examined. Furthermore, the contribution of each P450 enzyme to tolbutamide metabolism was investigated by using recombinant P450 enzymes. Although cytochrome P450 (CYP) 2C8, 2C9, and 2C19 metabolized tolbutamide, the main enzyme involved was CYP2C9. The K(i) values of several sulfonamides were comparable between human liver microsomes and recombinant CYP2C9. The maximum unbound plasma concentration of sulfonamides in the portal vein was calculated from literature data on the pharmacokinetics of sulfonamides. Using the K(i) values obtained from in vitro inhibition studies, the degree of increase in tolbutamide area under the plasma concentration-time curve (AUC) was predicted. About 4.8- and 1.6-fold increases in tolbutamide AUC were predicted by coadministration of sulfaphenazole and sulfamethizole, respectively, which agreed well with the reported increases in humans. Furthermore, the increase in tolbutamide AUC by coadministration of sulfadiazine, sulfisoxazole, and sulfamethizole was predicted to be 1.5- to 2. 6-fold, although the corresponding in vivo effects have not been reported. It is concluded that some of these sulfonamides have to be carefully coadministered with CYP2C9 substrates such as tolbutamide although coadministration of sulfaphenazole needs the greatest care.

Adult↗
PubMed1988

Relation between renal and hepatic excretion of drugs. XI. Excretion of sulfonamides with various physico-chemical properties of different ages--influence of nephrectomy or bile duct ligation.

The pharmacokinetics of a series of 6-sulfonamides, with gradually increasing molecular weights, were studied in anaesthetized rats after intravenous bolus injection. Immature (20-day-old) and adult (55-day-old) rats were compared. In both age groups renal excretion of all sulfonamides tested here dominates (about 5- to 10-fold). In 20-day-old rats renal and hepatic excretions are immature and reach about 50% (liver) or 30% (kidney) of adult values. Relation between renal and hepatic excretion of sulfonamides is strongly correlated to the lipophilicity of these substances. Hepatic excretion of sulfonamides seems to be correlated to their pKa-values. Concerning their excretion via urine it is necessary to correlate different steps of renal transport to physico-chemical properties in detail. A general correlation between renal excretion of sulfonamides and their chemical structure obviously does not exist. After bile duct ligation 24 h before clearance experiments no compensatory increase of renal sulfonamide excretion occurs. 24 h following bilateral nephrectomy hepatic excretion of sulfonamides is significantly enhanced; however, this phenomenon is related to physico-chemical properties of the sulfonamides. Age differences in compensation of one elimination pathway do not exist.

Aging↗
PubMedDate not supplied

Liquid chromatographic determination of multiple sulfonamide residues in bovine milk: collaborative study.

A collaborative study involving 8 laboratories was conducted on the determination of 8 sulfonamide residues in raw bovine milk using a liquid chromatographic (LC) method. The sulfonamides are extracted with chloroform-acetone, the organic phase is evaporated, the residues are dissolved in an aqueous potassium phosphate solution, and the fatty residues are removed by washing with hexane. The aqueous layer is collected, filtered, and injected onto an LC system, and the analyte is detected by ultraviolet (UV) absorption at 265 nm. To quantitate all 8 sulfonamides isocratically, 2 chromatographic conditions are required: 12% methanol in the mobile phase for 5 sulfonamides, and 30% methanol in the mobile phase for 4 sulfonamides. Sulfamethazine (SMZ), the most widely used sulfonamide, is detected by both systems. Collaborators were instructed to analyze 3 replicates each of control milk and control milk fortified at 3 levels. They were also provided with 20 blind incurred samples (10 samples in duplicate) to analyze. For 10 ppb fortified milk, the average interlaboratory recovery for the 8 sulfonamides ranged from 56.2% for sulfaquinoxaline (SQX) to 82.7% for SMZ in the 12% methanol mobile phase (SMZ12). Also at this level, Sr ranged from 3.2 for SQX to 8.9 for SMZ12, and SR ranged from 6.9 for sulfadimethoxine to 17.2 for SMZ in the 30% methanol system (SMZ30). At 10 ppb, RSDr and RSDR ranged from 5.7% for SQX to 10.8% for SMZ12, and 10.1% for sulfamerazine to 20.9% for SMZ30, respectively. These results demonstrate that the method is suitable for the determination of the 8 sulfonamide residues in milk at 10 ppb. However, the identification of positives by this procedure needs additional confirmation by procedures comparable to the specificity achievable by liquid or gas chromatography combined with mass spectrometry.

Acetone↗
PubMed1994

In vitro susceptibility of equine Salmonella strains to trimethoprim and sulfonamide alone or in combination.

The in vitro activity of trimethoprim (TMP) and 9 sulfonamides and their combinations in 6 concentration ratios was tested against 62 Salmonella strains isolated from horses over a 3-year period in the Netherlands, using the agar-dilution method. Most of the isolates were S typhimurium strains (n = 52); the others were S heidelberg (n = 3), S hadar (n = 2), S thompson (n = 2), S enteritidis (n = 1), S infantis (n = 1), and S derby (n = 1). The minimal TMP concentration at which 50% of the Salmonella strains were inhibited (MIC50) was 0.12 micrograms/ml. Sulfachlorpyridazine (SCP; MIC50, 16 micrograms/ml), sulfamethoxazole (SMX; MIC50, 32 micrograms/ml), and sulfadiazine (SDZ; MIC50; 32 micrograms/ml) were the most potent of the sulfonamides tested. The antimicrobial effect of the sulfonamides, in combination with TMP (additive, synergistic, or antagonistic), was expressed by the fractional inhibitory concentration (FIC) index. Concentrations of SDZ and SCP with TMP had marked synergism at all tested TMP-to-sulfonamide concentration ratios (1:1 to 1:160; FIC index, 0.10 to 0.50); SMX had synergy with TMP at all ratios, except 1:1 (FIC index, 0.10 to 0.27). Sulfamethazine, sulfamerazine, sulfadoxine (SDX), sulfatroxazole, sulfadimethoxine, and sulfacetamide had MIC50 greater than their breakpoint MIC value and are, therefore, less potent drugs. However, synergy with TMP was found for these less potent sulfonamides at certain concentration ratios, depending on the sulfonamide used. Sixteen Salmonella strains were resistant to TMP, all sulfonamides, and TMP-sulfonamide combinations; 14 of these strains were S typhimurium phage type 200, 1 was S typhimurium phage type 61, and 1 was S typhimurium phage type 10.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗