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PubMed1999

Carbonic anhydrase inhibitors. Water-soluble, topically effective intraocular pressure lowering agents derived from isonicotinic acid and aromatic/heterocyclic sulfonamides: is the tail more important than the ring?

Reaction of twenty aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with isonicotinoyl chloride afforded a series of water-soluble compounds (as hydrochloride or triflate salts). The new derivatives were examined as inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form). Efficient inhibition was observed against all three isozymes, but especially against CA II and CA IV (K(I) in the nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the most potent inhibitors synthesized were applied as 2% water solutions directly into the eye of normotensive or glaucomatous albino rabbits. Very strong intraocular pressure (IOP) lowering was observed for many of them, and the active drug was detected in eye tissues and fluids. According to others the IOP lowering effect of topically effective antiglaucoma sulfonamides is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best studied case e.g. dorzolamide. In order to prove that the tail (in this case the isonicotinoyl moiety) conferring water solubility to a sulfonamide CA inhibitor is more important than the ring to which the sulfonamido group is grafted a dorzolamide derivative to which the isonicotinoyl moiety was attached was also prepared. This new compound is more water soluble than dorzolamide (as hydrochloride salt), behaves as a strong CA II inhibitor and acts similarly to the parent derivative in lowering IOP in experimental animals. Thus, it seems that the tail conferring water solubility is more important for topical activity as an antiglaucoma drug than the heterocyclic/aromatic ring to which the sulfonamido moiety is attached.

Administration, Topical↗

PubMed1996

Field detection of sulfonamides in urine: the development of a new and sensitive test.

A new, field-adapted, colorimetric method for detecting sulfonamide drugs in urine is described. The method uses the color reagent, p-dimethylaminocinnamaldehyde, and has a detection limit of about 1 microgram/ml. Analysis of 35 samples collected in the field, comparing results obtained with the colorimetric field test with those obtained using high-performance liquid chromatography, indicated a calculated sensitivity value of 94% and a specificity value of 94% for the test to detect the presence of sulfonamides. The field test can be modified to allow quantitation of sulfonamides in urine in field situations, using a hand-held, portable photometer for measuring the absorbance of test solutions. For this test, calculated coefficients of variation for day to day reproducibility were < or = 5% at sulfonamide concentrations > or = 3 micrograms/ml. This new test for detecting the presence of sulfonamides in urine is more sensitive and reliable than the presently used Bratton-Marshall test.

Chromatography, High Pressure Liquid↗

PubMed1993

Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines.

OBJECTIVE: To determine whether erythromycins, sulfonamides, and tetracyclines are associated with an increased risk for acute hepatitis. DESIGN: Case-control study. SETTING: Medicaid billing data from Michigan and Florida between 1980 and 1987. PATIENTS: The 107 cases included patients hospitalized with acute symptomatic hepatitis without an identifiable cause of liver disease noted in the medical record. Four controls per case were randomly selected and were matched for age, sex, and state. RESULTS: Five cases (4.7%) and four controls (0.9%) were exposed to erythromycins, yielding an odds ratio of 5.2 (95% Cl, 1.1 to 26.6). No case or control was exposed to erythromycin estolate. Eight cases (7.5%) and three controls (0.7%) were exposed to oral sulfonamides, yielding an odds ratio of 11.4 (Cl, 2.7 to 67.8). All (except one control) had received trimethoprimsulfamethoxazole. Five cases (4.7%) and four controls (0.9%) were exposed to tetracyclines, yielding an odds ratio of 5.2 (Cl, 1.4 to 19.7). The results did not change substantively for erythromycin or sulfonamides after adjustment using multiple logistic regression for age, sex, state, and use of other hepatotoxic drugs. With tetracyclines, however, the odds ratio decreased to 3.6 (Cl, 0.9 to 14.3). Associations were also seen with isoniazid (P = 0.008) and rifampicin (P = 0.04). The number of patients developing acute symptomatic liver disease resulting in hospitalization for each million patients treated with a 10-day course of erythromycin was 2.28 cases; for sulfonamides, this figure was 4.8 cases; and for tetracycline, the figure was 1.56 cases. CONCLUSION: Erythromycin, sulfonamides, and tetracyclines are associated with acute symptomatic hepatitis resulting in hospitalization. Given the widespread use of these drugs, they will be among the more common drugs associated with hepatitis.

Acute Disease↗

PubMedDate not supplied

Gas chromatographic-mass spectrometric determination of six sulfonamide residues in egg and animal tissues.

A gas chromatographic-mass spectrometric method using selected ion monitoring mode for simultaneous determination of 6 sulfonamides in egg and edible animal tissues has been developed. Sulfonamides are extracted from a sample with acetonitrile. The extract is passed through a silica cartridge column and concentrated. Diazomethane in ether is added to methylate sulfonamides. After evaporation, the residue is dissolved in methylene chloride and cleaned up by silica gel column chromatography. The methylene chloride eluate containing sulfonamide-methyl derivatives is evaporated to dryness, redissolved in ether and partitioned between 6N hydrochloric acid. The acid phase is made alkaline, extracted with ether, and the ether solution, after concentration, is analyzed by gas chromatography-mass spectrometry in selected ion monitoring mode. Average recoveries from egg and silver salmon fortified at 1 and 0.2 ppm levels with 6 sulfonamides are 99.2 and 84.3%, respectively; coefficients of variation are 7.03 and 11.20%, respectively. Detection limits are 0.01-0.05 ppm.

Animals↗

PubMed1989

In vitro antimicrobial activity of sulfonamides against some porcine pathogens.

The minimal inhibitory concentrations (MIC) of sulfonamides were determined against Bordetella bronchiseptica (n = 10), Pasteurella multocida (n = 10), Haemophilus pleuropneumoniae (n = 20), and Streptococcus suis (n = 10) strains isolated from pigs with atrophic rhinitis, pneumonia, or meningitis. Sulfonamides tested in an agar dilution method were sulfachloropyridazine, sulfadiazine, sulfadimethoxine, sulfamethazine, sulfadoxine, sulfisoxazole, sulfamerazine, sulfamethoxazole, sulfamethoxypyridazine, sulfanilamide, sulfatroxazole, and sulfisomidine. Results indicated that monotherapy of S suis infections with sulfonamides should not be encouraged because the MIC50 of all sulfonamides investigated was greater than 32 micrograms/ml. The MIC50 of the sulfonamides against B bronchiseptica ranged from 0.5 to 8 micrograms/ml, against P multocida from 2 to 32 micrograms/ml, and against H pleuropneumoniae from 8 to 64 micrograms/ml. The MIC50 of sulfachloropyridazine, sulfadiazine, sulfadimethoxine, sulfamerazine, and sulfamethoxazole for the gram-negative bacteria did not exceed 16 micrograms/ml. Among these compounds, sulfamethoxazole had the highest activity. The frequently prescribed sulfamethazine had an overall low antimicrobial activity.

Animals↗

PubMed1988

Synthesis and in vitro toxicity of hydroxylamine metabolites of sulfonamides.

Among the most serious side effects of sulfonamides are hypersensitivity reactions, the pathogenesis of which has been suggested to be mediated by reactive metabolites. We have previously demonstrated dose-related covalent binding and toxicity of reactive intermediates of sulfonamides generated by a murine hepatic microsomal activating system. We hypothesized that hydroxylamine (H/A) metabolites might be likely candidates for mediating such toxicity; accordingly, we synthesized chemically the H/As of sulfadiazine and sulfamethoxazole. Synthesis was performed using 4-nitrobenzenesulfonyl chloride and either 2-aminopyrimidine or 3-amino-5-methylisoxazole, respectively, as starting materials. The resulting nitro derivatives were reduced to the corresponding H/A with hydrogen in the presence of a poisoned platinum catalyst. After synthesis and purification, toxicity of the H/As to lymphocytes of normal volunteers was evaluated using three cytotoxicity assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye conversion, trypan blue dye exclusion and propidium iodide dye exclusion. The H/As of sulfadiazine and sulfamethoxazole displayed dose-related toxicity. 1.6 mM sulfadiazine H/A produced 82% cell death, whereas 400 microM sulfamethoxazole H/A produced 62% cell death; the parent sulfonamides were not toxic to cells. The toxicity of sulfamethoxazole H/A was decreased by coincubation with glutathione or N-acetylcysteine; there was a 47% decrease in toxicity when coincubated with 100 microM glutathione, whereas there was a 55% decrease displayed when coincubation was done with 500 microM N-acetylcysteine. H/A metabolites of the sulfonamides or their nitroso derivatives, normally detoxified by conjugation to glutathione, may be the proximate toxins mediating sulfonamide hypersensitivity.

Cell Survival↗

PubMed1995

Metabolic predisposition to cutaneous adverse drug reactions. Role in toxic epidermal necrolysis caused by sulfonamides and anticonvulsants.

BACKGROUND AND DESIGN: Cutaneous adverse drug reactions (ADRs) have been hypothesized to have a metabolic basis. Our aim was to identify detoxification defects involved in toxic epidermal necrolysis and other severe cutaneous ADRs. Lymphoid cells of 33 patients with cutaneous ADRs were challenged with reactive metabolites generated from drugs by a microsomal oxidation system. To be precise in the detoxification defect involved in sulfonamide and anticonvulsant reactions, we challenged lymphoid cells from 11 patients (seven patients with sulfonamide ADRs and four patients with anticonvulsants ADRs) to menadione and formaldehyde. Menadione induces toxic effects by oxygen species; formaldehyde is detoxified by aldehyde dehydrogenase, oxidase, and reductase. RESULTS: When the culprit drug was a sulfonamide or an anticonvulsant (used in 13 and 13 patients, respectively), the toxic effects of culprit drug-reactive metabolites toward patients' lymphoid cells were higher than toward controls'. First-degree relatives of four patients with sulfonamide- and phenobarbital-induced toxic epidermal necrolysis were also tested. In each family, a relative was more susceptible to culprit drug-reactive metabolites than were controls. After incubation with menadione, or formaldehyde, no difference in toxicity was found between patients' and controls' lymphoid cells. CONCLUSIONS: Toxic epidermal necrolysis and other severe cutaneous ADRs to sulfonamides and anticonvulsant drugs may be linked to a highly specific defect in the detoxification of culprit drug-reactive metabolites. Our results suggest that this defect is constitutional and inherited and does not involve oxygen free radicals and/or aldehyde detoxification pathways.

Adolescent↗

PubMed1997

Patients with delayed-onset sulfonamide hypersensitivity reactions have antibodies recognizing endoplasmic reticulum luminal proteins.

Sulfonamide antimicrobials cause a delayed-onset, hypersensitivity-type syndrome characterized by fever, skin rash and multiorgan toxicity occurring 7 to 14 days after initiation of therapy. The pathogenesis is believed to be immune-mediated. We investigated whether patients with delayed-onset sulfonamide hypersensitivity reactions had antibodies recognizing hapten-microsomal protein conjugates and/or native microsomal proteins. By immunoblotting using rat liver as a source of microsomal protein, 17 of 21 patients had antibodies recognizing one or more of three native endoplasmic reticulum proteins of 55 kDa (14 of 21 patients), 80 kDa (4 of 21 patients) or 96 kDa (3 of 21 patients) in size on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. No control subjects (n = 11) and only 1 of 18 patients with adverse events not consistent with sulfonamide hypersensitivity reactions had antibodies against these microsomal proteins under the conditions used. Only 1 patient had antibodies that recognized the sulfonamide hapten, sulfamethoxazole. The 55-kDa protein was identified as protein disulfide isomerase. The 80-kDa protein was identified as grp78. The 96-kDa protein was not identified. Delayed-onset sulfonamide hypersensitivity reactions are therefore primarily associated with antibodies recognizing specific protein epitopes and not anti-drug antibodies.

Animals↗

PubMed1994

Drug-protein interactions. Refined structures of three sulfonamide drug complexes of human carbonic anhydrase I enzyme.

N-unsubstituted sulfonamide drugs are widely used for opthalmic disorders. Inhibition of carbonic anhydrase enzyme is believed to be the chief reason for their therapeutic effects. Structures of three such sulfonamide drugs complexed to human carbonic anhydrase I enzyme (HCAI) refined crystallographically at 2 A resolution are reported here. The drug molecules are all bound in the active site of the enzyme, but among themselves show differences in the orientations of the sulfamido groups interacting with the essential zinc ion in the active site. The activity linked solvent molecule coordinated to zinc in the native enzyme is displaced by all the three sulfonamides. The active site loop of Leu198, Thr199 and His200 has been identified to be important for binding of the drug molecules due to their appreciable atomic displacements and intra-molecular hydrogen bonds arising out of their interactions with the sulfonamides. These interactions along with active site charge requirements are proposed to be responsible for the orientational differences of the sulfamido groups and also for differences in the inhibitory powers of the drugs. A hydrogen bond network involving solvent molecules and active site residues His200 and His67 amongst others in the native enzyme, is disrupted upon binding of methazolamide but not in the other two sulfonamides. This is the first crystallographic evidence of the possible involvement of His200 in the inhibition of HCAI. An important role of Thr199 in distinguishing between the substrate and inhibitor binding modes of HCO3- to the enzyme at high pH is also inferred.

Acetazolamide↗

PubMed2000

Unusual electronic effects of electron-withdrawing sulfonamide groups in optically and magnetically active self-assembled noncovalent heterodimetallic d-f podates.

The segmental ligand 2-(6-(N,N-diethylcarbamoyl)pyridin-2-yl)-1,1'-dimethyl-2'-(5-(N,N-diethylsulfonamido)-pyridin-2-yl)-5,5'-methylenebis[1H-benzimidazole] (L3) is synthesized via a multistep strategy that allows the selective introduction of an electron-withdrawing sulfonamide group into the ligand backbone and its subsequent hydrolysis to the hydrophilic sulfonate group. Compared to that of the methylated analogue L1, the affinity of the bidentate binding unit of L3 for H+ and for trivalent lanthanide ions (LnIII) in [Ln(L3)3]3+ and [Ln2(L3)3]6+ is reduced because the electron-withdrawing sulfonamide substituent weakens sigma-bonding, but improved retro-pi-bonding between the bidentate binding units of L3 and soft 3d-block ions (M(II) = FeII, ZnII) overcomes this effect and leads to homometallic complexes [Mn(L(i))m]2n+ (i = 1, 3) displaying similar stabilities. Theoretical ab initio calculations associate this dual effect with a global decrease in energy of pi and sigma orbitals when the sulfonamide group replaces the methyl group, with an extra stabilization for the LUMO (pi). The reaction of L3 with a mixture of LnIII and M(II) (M = Fe, Ni, Zn) in acetonitrile gives the noncovalent podates [LnM(L3)3]5+ in which LnIII is nine-coordinated by the three wrapped tridentate segments, while the bidentate binding units provide a facial pseudooctahedral site around M(II). The X-ray structure of [EuZn(L3)3](ClO4)4(PF6)(CH3NO2)3(H2O) reveals that the bulky sulfonamide group at the 5-position of the pyridine ring only slightly increases the Zn-N bond distances as a result of sigma/pi compensation effects. The introduction of spectroscopically and magnetically active FeII and NiII into the pseudooctahedral site allows the detailed investigation of the electronic structure of the bidentate segment. Absorption spectra, combined with electrochemical data, experimentally demonstrate the dual effect associated with the attachment of the sulfonamide group (decrease of the sigma-donating ability of the pyridine lone pair and increase of the pi-accepting properties of the coordinated bidentate binding unit). The influences on the ligand field strength and on tunable room-temperature FeII spin-crossover processes occurring in [LnFe(L3)3]5+ are discussed, together with the origin of the entropic control of the critical temperature in these thermal switches.

Journal Article↗

PubMed2000

Sulfonamide resistance: mechanisms and trends.

Sulfonamides were the first drugs acting selectively on bacteria which could be used systemically. Today they are infrequently used, in part due to widespread resistance. The target of sulfonamides, and the basis for their selectivity, is the enzyme dihydropteroate synthase (DHPS) in the folic acid pathway. Mammalian cells are not dependent on endogenous synthesis of folic acid and generally lack DHPS. Instead, they have a folate uptake system which most prokaryotes lack. Laboratory mutants in the dhps (folP) gene can be easily isolated and show a trade off between sulfonamide resistance and DHPS enzyme performance. Clinical resistant mutants, however, have additional compensatory mutations in DHPS that allow it to function normally. In many pathogenic bacteria sulfonamide resistance is mediated by the horizontal transfer of foreign folP or parts of it. Clinical resistance in gram-negative enteric bacteria is plasmid-borne and is effected by genes encoding alternative drug-resistance variants of the DHPS enzymes. Two such genes, sul1 and sul2, have been sequenced and are found at roughly the same frequency among clinical isolates. Remarkably, the corresponding DHPS enzymes show pronounced insensitivity to sulfonamides but normal binding to the p -aminobenzoic acid substrate, despite the close structural similarity between substrate and inhibitor. Copyright 2000 Harcourt Publishers Ltd.

Journal Article↗

PubMed2003

A randomized, pilot trial comparing full versus escalating dose regimens for the desensitization of AIDS patients allergic to sulfonamides.

UNLABELLED: Sulfonamides are drugs extensively used in the management of AIDS patients. However, the use of sulfonamides is often associated with the development of allergic reactions, provoking the substitution of the drug (by another that may be less effective); alternatively attempts are made to desensitize the patient. OBJECTIVE: Compare two drug regimens (full vs. escalating doses) for the oral desensitization of AIDS patients allergic to sulfonamides. MATERIAL AND METHODS: AIDS patients with previous allergic reactions to sulfonamides and requiring prophylaxis against Pneumocistis carinii, central nervous system toxoplasmosis and diarrhea caused by Isospora belli were randomly assigned to a group receiving a routine dose of cothrimoxazole, or another that received escalating doses of an oral suspension of the same drug, initiating with 75 mg/day of sulfamethoxazole that was doubled every 48 hours till the full dose was reached, if no allergic reaction occurred. Patients were monitored for at least 6 months after enrollment in the trial. The major end-point was the ability to maintain prophylactic treatment after that period of time. Plasma viral load (PVL) and CD(4)/CD(8) counts were measured at baseline. Liver enzymes and hematological parameters were measured at baseline and after 1, 3 and 6 months. RESULTS: Eighteen patients were enrolled in the study (15 men and 3 women), with ages ranging from 30 to 57 years (mean 39.9). The mean CD(4) counts were slightly higher for patients receiving a full dose; there was also a trend towards higher baseline CD(8) counts among patients developing new reactions. The mean PVL was similar among the patients in both desensitization groups. The incidence of new allergic reactions was identical (40%) in the two groups. All adverse reactions were mild and no significant increase in liver enzymes were observed. CONCLUSION: Dose regimen is not a predictor of the development of new allergic reactions amongst patients challenged with sulfonamides after an initial allergic reaction.

AIDS-Related Opportunistic Infections↗

PubMed1996

Multiresidue determination of sulfonamide antibiotics in milk by short-column liquid chromatography coupled with electrospray ionization tandem mass spectrometry.

Liquid chromatography coupled to electrospray mass spectrometry and tandem mass spectrometry has been used for the determination and quantification of 21 sulfonamides and two potentiators (ormethoprim, trimethoprim) in milk. Separation using high-performance liquid chromatography was achieved in less than 6 min for all compounds on a short (4.0 x 50 mm, 3 micron) reversed-phase column. After sample clean-up, time-scheduled single-ion monitoring (SIM) yielded detection of sulfonamides in milk from low ppb level to the ppt level. The strategy used to detect, confirm and quantify sulfonamides in milk samples was as follows: (a) pre-screening (and cp3firmation) of target and non-target sulfonamides by precursor ion scan and/or multiple reaction monitoring experiments using generic product ions; (b) quantification of identified target compounds by monitoring their protonated molecule ions in a time-scheduled SIM experiment; (c) further confirmation, if necessary, by selected reaction monitoring using characteristic product ions.

Animals↗

PubMed2000

Determination of eight sulfonamides in bovine kidney by liquid chromatography/tandem mass spectrometry with on-line extraction and sample clean-up.

A sensitive, high performance liquid chromatography/tandem mass spectrometric (i.e. mass spectrometry/mass spectrometry; LC/MS/MS) method with on-line extraction and sample clean-up for the screening and confirmation of residues of sulfonamides in kidney is described. The sulfonamides are extracted from homogenized kidney with methanol. After centrifugation of the extract, an aliquot of the extract is directly injected on the LC/MS/MS system with further extraction and clean-up of the sample on-line. Detection of the analytes was achieved by positive electrospray ionization (ESI) followed by multiple reaction monitoring. For each sulfonamide the collisional decomposition of the protonated molecule to a common, abundant fragment ion was monitored. The method has been validated for sulfadimethoxine, sulfaquinoxaline, sulfamethazine, sulfamerazine, sulfathiazole, sulfamethoxazole, sulfadiazine and sulfapyridine. Calibration curves resulting from spiked blank kidney samples at the 10-200 microg/kg level showed good linear correlation. At the level of 50, 100 and 200 microg/kg both within- and between-day precision, as measured by relative standard deviation (RSD), were less than 16%. The limits of detection (LODs) ranged from 5 to 13.5 microg/kg. The recoveries ranged from 78 to 82%. The procedure provides a rapid, reliable and sensitive method for the determination of residues of sulfonamides in bovine kidney. The advantage of this method over existing methods is its decreased sample preparation and analysis time, which makes the method more suitable for routine analysis.

Animals↗

PubMed1984

Structure-activity relationships of sulfonamide drugs and human carbonic anhydrase C: modeling of inhibitor molecules into the receptor site of the enzyme with an interactive computer graphics display.

We have analyzed the molecular interaction of 28 sulfonamide inhibitors with human carbonic anhydrase C (HCAC) using an interactive computer graphic display. Small aromatic sulfonamides gain most of their inhibitory power towards HCAC from the interaction of hydrogen bond acceptors at the para or meta positions with hydrophilic residues of the enzyme. Additional coordinated water molecules stabilize the complexes of heterocyclic sulfonamides (i.e., thiophenes, 1,3-thiazoles, and 1,3,4-thiadiazoles) with HCAC. We propose two different modes of binding of the heterocyclic ring with respect to the active site cleft: the heterocyclic sulfur atom of a 3,4-unsubstituted thiophene approaches the oxygen atom of a coordinated water molecule (sulfur "out"), whereas in 3,4-unsubstituted 1,3,4-thiadiazoles, the sulfur is in contact with a hydrophobic part of the receptor site (sulfur "in"). This proposal is consistent with crystallographic evidence. Sulfonamides with two aromatic or heterocyclic rings also interact with a hydrophobic pocket of the enzyme located greater than 10 A away from the active site metal Zn2+. We also discuss the possibility that the relative inactivity of thiazide diuretics is due to the steric interaction of the ortho chlorine atom with the enzyme receptor cavity.

Binding Sites↗

PubMedDate not supplied

Influence of obesity on sulfonamide disposition in Zucker rats.

The genetically obese Zucker rat was used as a model of obesity and compared to its lean littermate to assess and quantify obesity-altered changes in the in vivo disposition of six sulfonamides. Body composition determination indicated that the obese rats were twice the weight of lean rats and a distinct trend towards an increase in fat free mass and total body water was observed. The sulfonamide blood concentration was measured by colorimetry after a 7 mg/kg intravenous dose. All sulfonamides exhibited a biexponential decline of blood concentration with time. The volume of distribution and clearance of sulfanilamide in lean and obese rats were similar resulting in similar elimination half-lives. A decrease in clearance coupled with a trend towards an increase in volume of distribution prolonged the elimination half-life of sulfadiazine in obese rats. For sulfapyridine, sulfamerazine, sulfisomidine and sulfisoxazole, increases in the volumes of distribution and clearances resulted in similar elimination half-lives in lean and obese rats. The free fractions of the sulfonamides were significantly increased in the serum of obese rats, the influence of which on the volume of distribution and clearance is discussed.

Animals↗

PubMedDate not supplied

Quantitative structure--pharmacokinetic relationship of a series of sulfonamides in the rat.

The pharmacokinetics of a series of sulfonamides were investigated after intravenous administration of a 7 mg/kg dose of individual sulfonamides to cannulated female lean Zucker rats. The concentrations of the sulfonamides in blood were determined by colorimetry. The blood concentration-time curves were fitted to a biexponential equation. The partition coefficient, log P, and pKa values of the sulfonamides were taken from the literature, log P and pKa values differed markedly across the series. The extent of protein binding varied enormously, increasing with partition coefficient. There was no significant relationship between the volume of distribution and partition coefficient. However, when the influence of protein binding on volume of distribution was eliminated, a significant linear relationship emerged. Total clearance formed a relatively complex nonlinear relationship with partition coefficient. The relationship of elimination half-life and partition coefficient was inverse of that between clearance and partition coefficient because of a lack of significant relationship between volume of distribution and partition coefficient.

Animals↗

PubMed1990

Chemical and pharmacological properties of MK-927, a sulfonamide carbonic anhydrase inhibitor that lowers intraocular pressure by the topical route.

A large number of sulfonamides have now been tested by the topical route for the lowering of intraocular pressure in the normal albino rabbit. Certain compounds with favorable balance between lipid and water solubility, and high activity against carbonic anhydrase, do lower pressure as much as 3 mmHg. MK-927, a thienothiopyrane-2-sulfonamide carrying an alkylamino group of pK 5.8, has desirable physicochemical properties: good water solubility below pH 5.8, a CHCl3/buffer ratio of 0.6 at pH 5.4, and a KI value against carbonic anhydrase of 2-7 nM, depending on assay conditions. Inhibition of CO2 hydration is non-competitive. By comparison with other candidate topically active sulfonamides, it is the most effective in terms of pressure lowering times duration of action. There are no apparent systemic effects or ocular toxicity. The concentration of drug reaching the ciliary process and aqueous humor is of the same order as that following parenteral sulfonamides, so that inhibition of the enzyme exceeds 99%. MK-927 is therefore a candidate for the clinical treatment of glaucoma.

Administration, Topical↗