Polymorphism in gene for microsomal epoxide hydrolase and lung disease.
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Epoxide Hydrolases↗
Biomedical subjects
B K Park
Publications and source records attributed to B K Park.
In vitro metabolism of dexamethasone (DEX) in human liver and kidney: the involvement of CYP3A4 and CYP17 (17,20 LYASE) and molecular modelling studies.
Dexamethasone (DEX) has previously been shown to be extensively metabolised to 6-hydroxylated and side-chain cleaved metabolites in human liver in vitro. CYP3A4 is responsible for 6alpha- and 6beta-hydroxylation of DEX and CYP17 is thought to mediate side-chain cleavage to generate 9alphafluoro-androsta-1,4-diene-11beta-hydroxy-16alpha-methyl-3,17-dione (9alphaF-A). Although 9alphaF-A has not previously been isolated as a metabolite in its unhydroxylated form in human liver incubations, it is formed as an intermediate metabolite, which is subsequently rapidly hydroxylated to OH-9alphaF-A. A main part of this study has been to conclusively show that DEX undergoes extensive side-chain cleavage to form 9alphaF-A in human kidney fractions, which is in contrast to profiles obtained for DEX metabolism in parallel human liver microsomal incubations where 6-hydroxylation is the predominant pathway. Furthermore, molecular models of CYP3A4 and CYP17 (17,20 lyase) have been used to model the enzyme fits of DEX. From these modelling studies it has been shown that DEX complements both putative enzyme active sites in orientations likely to lead to the formation of the metabolites identified in vitro. We have also been able to rationalise the preferential formation of the 6betaOH-DEX isomer.
Binding Sites↗
Evaluation of the effects of nursery depopulation on the persistence of porcine reproductive and respiratory syndrome virus and the productivity of 34 farms.
Nursery depopulation has been described as an effective strategy for improving the performance of weaned pigs. In order to assess whether the strategy was effective under a wide range of conditions, a study was carried out on 34 farms in the USA. Four groups with different depopulation protocols were designed on the basis of the location of the depopulated facility (on site vs off site) and the period for which the nursery remained empty (seven days vs 14 days). The changes in average daily liveweight gain, percentage mortality, feed efficiency and treatment cost per pig produced were assessed 12 months before and after nursery depopulation. The ability to eliminate porcine reproductive and respiratory syndrome (PRRS) virus was examined by indirect fluorescent antibody testing of the nursery pigs. Significant improvements (P < 0.0001) were detected in both average daily gain and percentage mortality after depopulation when the differences within an individual group were analysed, but no significant differences (P > 0.14) were observed between the study groups. Serological testing indicated that antibodies to PRRS virus were still present in 14 of the 34 farms after depopulation.
Animals↗
Structural basis for the haemotoxicity of dapsone: the importance of the sulphonyl group.
The structural basis of dapsone (4,4'-diaminodiphenyl sulphone) haemotoxicity has been determined by investigation of the in vitro bioactivation of a series of 4-substituted arylamines. In the presence of rat liver microsomes, dapsone (100 microM) was the most potent former of methaemoglobin in human erythrocytes (44.8 +/- 6.7%). Substitution of the sulphone group with sulphur (11.6 +/- 1.4% methaemoglobin), oxygen (4.5 +/- 1.1%), nitrogen (0.0 +/- 3.2%), carbon (13.6 +/- 0.8%) or a keto group (34.0 +/- 6.1%) resulted in a decrease in methaemoglobin formation. Only one compound, 4,4'-diaminodiphenylamine, generated significant (P < 0.001) amounts of methaemoglobin (25.6 +/- 2.5%) in the absence of NADPH. To assess further the role of the 4-substituent in methaemoglobinaemia, the toxicity of a series of 4-substituted aniline derivatives was also studied. Of the anilines studied, 4-nitroaniline caused the most methaemoglobin (36.5 +/- 8.0%), whilst aniline caused the least (0.3 +/- 0.5%). Overall, there was a significant correlation (r2 = 0.83) between the haemotoxicity and the Hammett constant, sigma(p), suggesting that it is the electron-withdrawing properties of the substituent that influence the methaemoglobin formation. In the presence of microsomes prepared from two human livers, dapsone was the most haemotoxic bis arylamine, whereas 4-iodoaniline was the most potent methaemoglobin former (60.6 and 73.6%) and aniline the least potent (1.1 and 2.4%). As a whole, these results indicate that the sulphonyl group, which is essential for the pharmacological activity of dapsone, is also largely responsible for the haemotoxicity seen with this drug.
Animals↗
Synthesis, antimalarial activity, and molecular modeling of tebuquine analogues.
Tebuquine (5) is a 4-aminoquinoline that is significantly more active than amodiaquine (2) and chloroquine (1) both in vitro and in vivo. We have developed a novel more efficient synthetic route to tebuquine analogues which involves the use of a palladium-catalyzed Suzuki reaction to introduce the 4-chlorophenyl moiety into the 4-hydroxyaniline side chain. Using similar methodology, novel synthetic routes to fluorinated (7a, b) and a dehydroxylated (7c) analogue of tebuquine have also been developed. The novel analogues were subjected to testing against the chloroquine sensitive HB3 strain and the chloroquine resistant K1 strain of Plasmodium falciparum. Tebuquine was the most active compound tested against both strains of Plasmodia. Replacement of the 4-hydroxy function with either fluorine or hydrogen led to a decrease in antimalarial activity. Molecular modeling of the tebuquine analogues alongside amodiaquine and chloroquine reveals that the inter-nitrogen separation in this class of drugs ranges between 9.36 and 9.86 A in their isolated diprotonated form and between 7.52 and 10.21 A in the heme-drug complex. Further modeling studies on the interaction of 4-aminoquinolines with the proposed cellular receptor heme revealed favorable interaction energies for chloroquine, amodiaquine, and tebuquine analogues. Tebuquine, the most potent antimalarial in the series, had the most favorable interaction energy calculated in both the in vacuo and solvent-based simulation studies. Although fluorotebuquine (7a) had a similar interaction energy to tebuquine, this compound had significantly reduced potency when compared with (5). This disparity is possibly the result of the reduced cellular accumulation (CAR) of fluorotebuquine when compared with tebuquine within the parasite. Measurement of the cellular accumulation of the tebuquine analogues and seven related 4-aminoquinolines shows a significant relationship (r = 0.98) between the CAR of 4-aminoquinoline drugs and the reciprocal of drugs IC50.
Aminoquinolines↗
Bioactivation and inactivation of aflatoxin B1 by human, mouse and rat liver preparations: effect on SCE in human mononuclear leucocytes.
The purpose of this study was to investigate the use of human and animal subcellular liver fractions in an in vitro evaluation of carcinogenic risk. The bioactivation and bioinactivation of the known genotoxic carcinogen aflatoxin B1 by human, mouse and rat liver preparations was investigated using the SCE assay in human lymphocytes as a genotoxic endpoint. There was a 10-fold variation in SCE response (1.1-11.6 SCE/Cell) in human mononuclear leucocytes (MNLs) after aflatoxin B1 was activated by human liver microsomes (n = 6). Activation correlated with the CYP1A2 phenotype of livers (r = 0.8; p < 0.05), but there was no correlation with either GST M1 genotype or epoxide hydrolase phenotype. Mouse liver microsomes activated aflatoxin B1 to a greater extent [(1 micro M) 12.8 +/- 2.51 SCE/Cell] than either rat [(10 micro M) 12.0 +/- 3.84 SCE/Cell or human (L25) [(10 micro M) 8.8 +/- 2.00 SCE/Cell liver microsomes. The addition of mouse liver cytosol and reduced glutathione (GSH) significantly (p < 0.001) reduced aflatoxin B1-dependent genotoxicity, whereas the addition of either human or rat cytosol (+GSH) was without effect. These data indicate that species variation in both bioactivation and bioinactivation can exist. Therefore there is a necessity for careful selection of activation systems from species whose biochemical profile reflects that of man.
Aflatoxin B1↗
Gait electromyography in children with myelomeningocele at the sacral level.
OBJECTIVE: Patients with sacral level myelomeningocele can be expected to maintain a high level of ambulatory status long into adulthood. Gait deterioration and knee pain reported in this population may be attributed to compensatory movements and increased recruitment of less affected muscle groups to achieve this desired level of ambulation. The objective of this study was to analyze the effect of the solid ankle-foot-orthoses (AFOs) on the muscular activity of selected muscles during walking. DESIGN: Cohort/outcome. SETTING: Laboratory. PATIENTS: Twenty four patients with sacral level myelomeningocele between 4 to 17 years of age. INTERVENTION: Electromyographic activity of selected muscle groups were studied during barefoot walking and walking with solid AFOs at a self-selected walking velocity. MAIN OUTCOME MEASURES: Timing of electromyographic activity and sagittal plane knee kinematics. Comparison to normal electromyographic patterns and changes between barefoot and AFO walking conditions. RESULTS: With the AFOs there was significantly less prolonged stance phase quadriceps activity compared with barefoot walking, although greater than normal activity persisted. There was no change between conditions for the other monitored muscle groups. All muscles elicited greater duration of activity over the course of the gait cycle. CONCLUSIONS: Our results show that solid AFOs improve the prolonged knee extensor activity evident for barefoot walking. This is clinically relevant to the gait deterioration and knee pain sometimes seen in this patient population. We espouse early and persistent orthotic intervention to reduce compensatory muscular overactivity and maintain gait quality.
Adolescent↗
Facet tropism in lumbar motion segments and its significance in disc herniation.
OBJECTIVE AND DESIGN: To define facet tropism (FT) for each motion segment of the lower lumbar spine for subjects without disc herniation, and to evaluate the significance of facet tropism in disc herniation. METHODS: Sixty subjects were evaluated by measuring the facet angle (FA) of three lower lumbar motion segments with the use of computed tomography (CT) and a computer program. The subjects were divided into two groups: 33 without disc herniation and 27 with disc herniation at one or more levels of lower lumbar motion segments. The FA was defined as the angle of the facet and midsagittal lines. The difference between the right and left FAs at each motion segment was calculated. FT was defined as an angle difference larger than the mean and one standard deviation of the angle differences between the right and left FAs at each motion segment in the group without disc herniation. OUTCOME MEASUREMENTS: Statistical significance of the bilateral angle difference of each lower lumbar motion segment between the two groups was analyzed by the two-sample t test. Using the defined angle difference for FT, the incidence of FT in the two groups at each motion segment was analyzed by the Fisher's exact test. RESULTS: FT was defined for the 33 subjects without disc herniation on CT scans as an angle difference larger than 12 degrees at L3-L4, 15 degrees at L4-L5, and 12 degrees at L5-S1, approximately. There was no statistical significance in the bilateral FA difference (p > .05) and incidence of FT (p > .05) at each segment between the two groups. CONCLUSION: This study did not show that facet joint tropism plays a significant role in disc herniation in the lower lumbar spine.
Adult↗
The metabolism of 16-fluoroestradiols in vivo: chemical strategies for restricting the oxidative biotransformations of an estrogen-receptor imaging agent.
16 alpha-Fluoro-17 beta-, 16 alpha-fluoro-17 alpha-, and 16 beta-fluoro-17 beta-[6,7-3H]estradiol were prepared from [6,7-3H]estrone via fluorination of 3,17-bis(tert-butyldimethylsilyloxy)-[6,7-3H]estratetraene with N-fluoropyridinium triflate and reduction of 16 alpha/beta-fluoro[6,7-3H]estrone with NaBH4. The three isomers were separated by silica-phase high-performance liquid chromatography. They were administered intravenously (4 mumol/kg to anaesthetized male rats. Their biliary metabolites (90-97% of dose over 6 h) were characterized by high performance liquid chromatography-mass spectrometry and compared with those of [6,7-3H]17 beta-estradiol. The four estrogens and their hydroxylated and methoxylated metabolites were excreted as glucuronides. C-16 fluorination blocked C-16 hydroxylated and also the dehydrogenation of the C-17 hydroxyl group. The 16 alpha-17 beta isomer was extensively glucuronylated at C(O)3 but also underwent aromatic hydroxylation and methoxylation before conjugation. Its C-17 epimer was subject to much greater aromatic hydroxylation but the catecholestrogen was O-methylated to a greater relative extent. The 16 beta-17 beta derivative underwent alicyclic as well as substantial aromatic hydroxylation and yielded numerous isomeric glucuronides of O-methylated catechols. Thus, the fluorine exerted complex effects (inhibitory and enhancing) on both localized (D-ring) and distal (A-ring) biotransformations of the estradiol molecule; the direction and magnitude of the effects being dependent upon the stereochemistry at C-16 and C-17. These findings provide structural guidelines for restricting the metabolism of tumor-imaging fluoroestrogens and thereby enhancing their delivery to the target tissue.
Animals↗
Indirect fluorescent IgM antibody response of pigs infected with porcine reproductive and respiratory syndrome syndrome virus.
IgG and IgM antibody responses were examined by an indirect fluorescent antibody method in pigs following inoculation with different porcine reproductive and respiratory syndrome virus (PRRSV) isolates or a vaccine virus. Viremia was also examined in the pigs. The IgG antibody was first detected between 9 and 14 days post inoculation (PI) and maintained high titers for at least 7 weeks PI. No change in IgG antibody titers was observed when the pigs were reinoculated with PRRSV 35 days PI. IgM antibody was detected between 5 and 28 days PI in the pigs. Reinoculation at 35 days PI caused a short term rise of IgM antibody. Virus was isolated from sera collected between 2 and 21 days PI. The IgM antibody was detected regularly in sera collected during viremia and up to 1-2 weeks after the viremic periods. These results suggest that pigs with detectable IgM antibody are probably pigs with recent infection and that routine testing of IgM antibody in purchased breeding pigs from seropositive farms may be useful in identification of pigs with recent infection.
Animals↗
Dexamethasone metabolism in vitro: species differences.
Dexamethasone (DEX) is extensively metabolized to 6-hydroxyDEX (6OH-DEX) and side-chain cleaved metabolites in human liver both in vitro and in vivo with CYP3A4 responsible for the formation of 6-hydroxylated products. In the present study, the metabolism of [3H]DEX has been examined in the liver fractions from various mammalian species and metabolite profiles compared with those obtained with human liver microsomes. Metabolites were quantified by radiometric high-pressure liquid chromatography (HPLC) and characterized by liquid chromatography-mass spectrometry (LC-MS) and co-chromatography with chemical standards, where available. 6OH-DEX formation was quantified for each species and the inhibitory potency of ketoconazole at 1 and 20 microM determined. Glycyrrhetinic acid, a specific inhibitor of 11-dehydrogenase, was also used to determine the extent of reductive DEX metabolism. Species differences in metabolite profiles obtained from microsomal incubations were both quantitative and qualitative. 6-Hydroxylation was variable (highest in the hamster) and was not always the major route of metabolism, and formation was sex-specific in the rat (male >> female). The inhibition of 6-hydroxylation (CYP3A) by ketoconazole was variable, and indicates that ketoconazole cannot be regarded as a selective inhibitor of CYP3A proteins in all species. Cytosolic incubations produced similar profiles in different species with the formation of a metabolite (M5) which was inhibited by glycyrrhetinic acid and tentatively identified in this study as 11-dehydro-side-chain cleaved DEX (11DH-9alphaF-A). In conclusion, the male rat gave a metabolite profile which was closest to that seen in the human. However, 6-hydroxylation was most extensive in the hamster which may therefore be a suitable model to use for further studies on DEX metabolism by CYP3A.
Administration, Topical↗
Development of a monoclonal antibody to 6 beta-hydroxycortisol and its application in an enzyme-linked immunosorbent assay (ELISA) for 6 beta-hydroxycortisol in urine.
A novel monoclonal antibody to 6 beta-hydroxycortisol (6 beta-OHC) was generated and incorporated into an antigen-coated indirect enzyme-linked immunosorbent assay (ELISA) using 6 beta-OHC-protein conjugate as the steroid-coating antigen. The monoclonal antibody is specific to 6 beta-OHC and 6 beta-OHC-3-carboxymethyloxime. Cross-reactivity with other structurally related steroids such as cortisol, cortisone, and 6 beta-hydroxycortisone was less than 10%. Two different clones (clone 5C1 and 19F) of the monoclonal anti-6 beta-OHC antibody have been developed, each with slightly different sensitivity and specificity. The sensitivity of the MAb clones was not significantly improved when compared to the rabbit polyclonal antibodies in this study, but still within the accepted detection limit for 6 beta-OHC in both human and laboratory animals. The assay had a detection limit of 200 ng/ml, an intraassay variation of 6.4% and an interassay variation of 7.3%. The application of the anti-6 beta-OHC-MAb-based-ELISA was tested by measuring the urinary output of 6 beta-OHC in human before and after enzyme induction by rifampicin treatment. The mean 24-h urine output of 6 beta-OHC in human subjects was 485 +/- 100 micrograms and 1478 +/- 281 micrograms before and after rifampicin administration, respectively. In conclusion, the monoclonal anti-6 beta-OHC antibody developed in this study has the required specificity and sensitivity as an alternative method for measuring urinary 6 beta-OHC in the detection of enzyme induction or enzyme inhibition of CYP3A in humans and laboratory animals.
Adult↗
Effects of Cryptosporidium baileyi infection on the bursa of Fabricius in chickens.
In order to clarify the effect of cryptosporidiosis on immune response, histopathological changes associated with experimentally occurring bursal cryptosporidiosis in chickens were chronologically observed as the first step. A total of 150 2-day-old chickens was each inoculated orally with a single dose of 5 x 10(5) Cryptosporidium baileyi oocysts. The chickens showed a normal profile of oocyst shedding in droppings. The bursa indices throughout the experimental period indicated negligible reactions. Numerous cryptosporidia occurred in the microvillous border of bursal epithelium between days 4 and 16 postinoculation (PI). Appearance of the most mast cells was followed by a dramatic loss of the protozoa in the bursa of Fabricius (BF). The distribution of the coccidium coincided with heterophil infiltration in the epithelium and adjacent lamina propria. The histopathological lesion was marked diffuse chronic superficial purulent bursitis with heterophil infiltration in the epithelium and adjacent lamina propria and mucosal epithelial hyperplasia. These results suggest that the bursitis may induce immunosuppressive effect.
Animals↗
Disposition of amodiaquine and related antimalarial agents in human neutrophils: implications for drug design.
The development and clinical use of 4-aminoquinoline antimalarial agents such as amodiaquine have been limited by toxicity to neutrophils. We have investigated the chemical basis of amodiaquine-induced toxicity and compared the findings with those for established antimalarial drugs proposed for human use. Amodiaquine, like chloroquine, mefloquine and halofantrine, was lysosomotropic and accumulated in human neutrophils. Amodiaquine did not lead to impairment of either cellular function or cell viability at therapeutic levels. In contrast to other antimalarial agents, amodiaquine (because it contains a 4-aminophenol function) depleted glutathione in activated neutrophils, by formation of an electrophilic quinoneimine metabolite. Bioactivation was accompanied by the expression of a drug-related antigen on the cell surface, which was recognized by drug-specific antibodies, suggesting that a type II hypersensitivity reaction is responsible for the observed toxicity. Similar bioactivation and accumulation were observed for the structurally related amopyroquine. The effects of chemical modifications at the 3'- and 5'-positions, which are known to enhance antimalarial activity, were also investigated. The introduction of a lipophilic 5'-chlorophenyl group and 3'-t-butyl group blocked bioactivation but enhanced cellular accumulation, with resultant impairment of function and neutrophil viability, whereas introduction of a second cationic dialkylamino group (bis-mannich compounds) blocked bioactivation and reduced cellular accumulation, without producing noticeable effects on cellular function and viability. These data provide a chemical rationale for the idiosyncratic agranulocytosis observed with amodiaquine, and they suggest that similar toxicity might be anticipated for amopyroquine but is less likely with bis-mannich antimalarial agents such as pyronaridine.
Amodiaquine↗
Induction of dual infections in newborn and three-week-old pigs by use of two plaque size variants of porcine reproductive and respiratory syndrome virus.
OBJECTIVE: To determine whether pigs can be dually infected with different plaque variants of porcine reproductive and respiratory syndrome virus (PRRSV). ANIMALS: 2 pregnant sows, 20 newborn pigs, and 20 three-week-old pigs. PROCEDURE: The 2 late-term pregnant sows were inoculated with the PRRSV small-plaque variant MN-Hs, and their pigs were challenge exposed at 7 days of age with the PRRSV large-plaque variant MN-HI. In addition, twelve 3-week-old pigs were inoculated with MN-Hs virus. Two groups of the pigs were challenge exposed with MN-HI virus at 14 and 42 days after initial inoculation. Virus was isolated from the pigs at various intervals, plaque sizes were examined, and serologic testing was performed. RESULTS: From the 2 groups of ten 7-day-old pigs, small-plaque PRRSV was isolated form 8 and 10 pigs. After subsequent challenge exposure, dual infections were diagnosed in 3 of 10 inoculated and 4 of 10 contact control pigs. In 3-week-old pigs infected with MN-Hs virus, dual infections were documented in 2 of 6 pigs when challenge exposed 14 days after initial infection. Virus was not isolated from sera of another 6 pigs challenge exposed 42 days after initial infection. Serum neutralization antibody was detected in all 6 pigs at challenge exposure. CONCLUSIONS: Dual infections were documented in viremic newborn pigs and 3-week-old pigs, using 2 plaque variants of PRRSV.
Animals↗
Development of a screening method for anti-6 beta-hydroxycortisol antibody using an enzyme-linked immunosorbent assay (ELISA) and its applications.
An indirect enzyme-linked immunosorbent assay (ELISA) for the detection of anti-6 beta-hydroxycortisol (6 beta-OHC) antibody has been developed. After immunization of 6 beta-OHC protein conjugates in New Zealand White rabbits, specific polyclonal antibody to 6 beta-OHC was detected by ELISA in which the wells of microtiter plates were coated with 6 beta-OHC conjugated to protein. The rabbit anti-6 beta-OHC antibody titer was above 1:500,000 dilution. Cross-reactivity with other structurally related steroids such as cortisol hydrocortisone was less than 5%. The sensitivity of the polyclonal antibody was comparable to previous studies reported, and was within the accepted detection limit for 6 beta-OHC in man and in laboratory animals. The assay has a low detection limit of 1 ng/ml, an intraassay variation of 3.1% and an interassay variation of 5.2%. The application of the anti-6 beta-OHC-based-ELISA to detect urinary 6 beta-OHC was tested by measuring the concentration of 6 beta-OHC in man before and after enzyme induction by rifampicin treatment. The mean 24 h urine output of 6 beta-OHC in man subjects was 370 +/- 105 micrograms and 1350 +/- 201 micrograms before and after rifampicin administration, respectively. This polyclonal anti-6 beta-OHC antibody-based ELISA can be modified to detect mouse anti-6 beta-OHC IgG with equally good precision and specificity which should be useful in screening positive clones of a 6 beta-OHC IgG secreting mouse hybridoma currently being developed for detecting enzyme induction of CYP3A4 in man and laboratory animals.
Adult↗
Characterization of the metabolites of carbamazepine in patient urine by liquid chromatography/mass spectrometry.
The urinary metabolites of carbamazepine (CBZ) in epileptic patients receiving long-term drug treatment have been characterized by LC/MS. CBZ-10,11-epoxide (9.6-15.0 micrograms/ml), trans-10, 11-dihydrodiol-CBZ (273.0-400.00 micrograms/ml), and CBZ (2.4-3.8 micrograms/ml) were measured by HPLC. The secondary N-glucuronide of CBZ, four phenolic O-glucuronides (including those of 2- and 3-OH-CBZ), two additional OH-CBZ O-glucuronides, and the N-glucuronide of CBZ-10,11-epoxide constituted the products of either direct conjugation or preliminary monoxygenation. Derivatives of these monoxygenated compounds, which were characterized as O-glucuronides, were represented by dihydroxylated (catechol) CBZ and its putative O-methyl metabolite and by 10,11-dihydrodiol-CBZ. 10,11-Dihydro-10-OH-CBZ O-glucuronide, a metabolite thought to be excreted only by uremic subjects, was not found. More complicated biotransformations of the 10,11-ene moiety were revealed by two carbinol products of azepine ring contraction: 9-OH-methyl-10-carbamoyl acridan and an hydroxylated derivative thereof, which were excreted as O-glucuronides. No polar sulfur-containing metabolites that might serve as indicators of reactive intermediate formation were found in human urine.
Adult↗
The relationship between the disposition and immunogenicity of sulfamethoxazole in the rat.
Idiosyncratic toxicity associated with sulfamethoxazole (SMX) is thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX-NOH) and further oxidation to the ultimate reactive metabolite, nitroso-sulfamethoxazole (SMX-NO). To establish the link between the formation of the ultimate reactive metabolite and SMX hypersensitivity, we have undertaken metabolism and immunogenicity studies in the rat by use of SMX and its metabolites. SMX was excreted in urine as N4-acetyl SMX and SMX-NOH, with approximately 10% remaining unchanged as parent amine. After administration of SMX-NOH (54 mg x kg(-1)) and SMX-NO (10 mg x kg(-1)), 38.3% and 46.1% of the doses, respectively, were excreted in urine as SMX and N4-acetyl SMX, which indicated extensive reduction of these metabolites in vivo. The immunogenic potential of SMX and its metabolites, SMX-NOH and SMX-NO, were assessed in rats by analyzing serum samples for the presence of anti-SMX IgG antibodies during a 4-week dosing period. No antibodies to SMX were detected in either control or SMX-treated rats. In contrast, a high titer of SMX-specific IgG antibody was present in sera from all the rats administered SMX-NO, reaching a maximum 14 to 21 days after the initial dose. Rats administered SMX-NOH only produced a weak IgG response after 3 weeks of dosing. These findings indicate that SMX-NO is highly immunogenic and may be responsible for the hypersensitivity reactions associated with SMX. Both SMX-NOH and SMX-NO undergo extensive reduction in vivo which may afford protection against SMX toxicity.
Animals↗