Biodegradation and metabolic pathway of sulfamethoxazole by Sphingobacterium mizutaii.

Sulfamethoxazole (SMX) is the most commonly used antibiotic in worldwide for inhibiting aquatic animal diseases. However, the residues of SMX are difficult to eliminate and may enter the food chain, leading to considerable threats on human health. The bacterial strain Sphingobacterium mizutaii LLE5 was isolated from activated sludge. This strain could utilize SMX as its sole carbon source and degrade it efficiently. Under optimal degradation conditions (30.8 °C, pH 7.2, and inoculum amount of 3.5 × 107 cfu/mL), S. mizutaii LLE5 could degrade 93.87% of 50 mg/L SMX within 7 days. Four intermediate products from the degradation of SMX were identified and a possible degradation pathway based on these findings was proposed. Furthermore, S. mizutaii LLE5 could also degrade other sulfonamides. This study is the first report on (1) degradation of SMX and other sulfonamides by S. mizutaii, (2) optimization of biodegradation conditions via response surface methodology, and (3) identification of sulfanilamide, 4-aminothiophenol, 5-amino-3-methylisoxazole, and aniline as metabolites in the degradation pathway of SMX in a microorganism. This strain might be useful for the bioremediation of SMX-contaminated environment.

Probing sulphamethazine and sulphamethoxazole based Schiff bases as urease inhibitors; synthesis, characterization, molecular docking and ADME evaluation.

In the current study, a novel series of Schiff base derivatives of (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (3a-3f) and (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (3g-3q) were synthesize. The structures of synthetic compounds were elucidated by various spectroscopic techniques such as FTIR, NMR and spectrometric HRMS analysis. Synthetic derivatives were evaluated for their Jack Bean urease inhibitory activity using established in-vitro assay. It is worth mentioning here that most of our derivatives of both series displayed moderate to strong inhibitory activity, ranging between IC50 = 2.48 ± 0.78 µM and 35.63 ± 1.26 µM, as compared to standard thiourea (IC50 = 20.03 ± 2.03 µM). Further, structure activity relationship studies suggest that the presence of halogen at ortho and para positions on the aryl ring in (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide derivatives and hydroxy and halogen in (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide derivatives increased the urease inhibitory activity. Furthermore, molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to urease. In order to evaluate drug likeness of compounds ADME evaluation was done, and the synthesized compounds were found to be non-toxic and present passive gastrointestinal absorption. The data suggests the synthesized sulphamethazine and sulphamethoxazole derivatives can serve as a novel scaffold to inhibit urease.

Sulfamethoxazole sorption by cattail and switchgrass roots.

Sorption to roots is one of several mechanisms by which plant-assisted attenuation of antibiotics can be achieved. The objectives of this study were to (1) evaluate the sorption of sulfamethoxazole (SMX) by cattail and switchgrass roots, (2) determine the kinetics of SMX sorption by cattail and switchgrass roots, and (3) characterize the temperature-dependency of SMX sorption. A batch sorption experiment was conducted to measure SMX sorption by roots of the two plant species using five initial antibiotic concentrations (2.5, 5, 10, 15, and 20 µg L-1) and eight sampling times (0, 0.5, 1, 2, 4, 8, 12, and 24 h). Another batch experiment was conducted at three temperatures (5, 15, and 25 °C) to determine the effect of temperature on sorption kinetics. SMX sorption followed pseudo-second-order kinetics. The pseudo-second-order rate constant (k2) decreased with increasing temperature for both plant species. The rate constant followed the order: 5 °C = 15 °C > 25 °C for cattail and 5 °C > 15 °C = 25 °C for switchgrass. Results from this study show that switchgrass roots are more effective than cattail roots in the removal of SMX. Therefore, the use of switchgrass in systems designed for phytoremediation of contaminants might also provide an efficient removal of some antibiotics.

Pharmacokinetics of Sulfamethoxazole and Trimethoprim During Venovenous Extracorporeal Membrane Oxygenation: A Case Report.

Extracorporeal membrane oxygenation (ECMO) therapy could affect drug concentrations via adsorption onto the oxygenator and/or associated circuit. We describe a case of a 33-year-old man with severe respiratory failure due to Pneumocystis jirovecii infection on a background of recently diagnosed human immunodeficiency virus infection. He required venovenous ECMO therapy for refractory respiratory failure. Intravenous sulfamethoxazole-trimethoprim (100 and 20 mg/kg/day) was administered in a dosing regimen every 6 hours. Pre-oxygenator, post-oxygenator, and arterial blood samples were collected after antibiotic administration and were analyzed for total sulfamethoxazole and trimethoprim concentrations. The peak sulfamethoxazole and trimethoprim concentrations were 122 mg/L and 5.3 mg/L, respectively. The volume of distribution for sulfamethoxazole was 0.37 and 2.30 L/kg for trimethoprim. The clearance for sulfamethoxazole was 0.35 ml/minute/kg and for trimethoprim was 1.64 ml/minute/kg. The pharmacokinetics of sulfamethoxazole and trimethoprim appear not to be affected by ECMO therapy, and dosing adjustment may not be required.

Pharmacokinetics of sulfamethoxazole and trimethoprim in Pacific white shrimp, Litopenaeus vannamei, after oral administration of single-dose and multiple-dose.

The tissue distribution and depletion of sulfamethoxazole (SMZ) and trimethoprim (TMP) were studied in Pacific white shrimp, Litopenaeus vannamei, after single-dose and multiple-dose oral administration of SMZ-TMP (5:1) via medicated feed. In single-dose oral administration, shrimps were fed once at a dose of 100 mg/kg (drug weight/body weight). In multiple-dose oral administration, shrimps were fed three times a day for three consecutive days at a dose of 100mg/kg. The results showed the kinetic characteristic of SMZ was different from TMP in Pacific white shrimp. In the single-dose administration, the SMZ was widely distributed in the tissues, while TMP was highly concentrated in the hepatopancreas. The t1/2z values of SMZ were larger and persist longer than TMP in Pacific white shrimp. In the multiple-dose administration, SMZ accumulated well in the tissues, and reached steady state level after successive administrations, while TMP did not. TMP concentration even appeared the downward trend with the increase of drug times. Compared with the single dose, the t1/2z values of SMZ in hepatopancreas (8.22-11.33h) and muscle (6.53-10.92h) of Pacific white shrimps rose, but the haemolymph dropped (13.76-11.03) in the multiple-dose oral administration. Meanwhile, the corresponding values of TMP also rose in hepatopancreas (4.53-9.65h) and muscle (2.12-2.71h), and declined in haemolymph (7.38-5.25h) following single-dose and multiple-dose oral administration in Pacific white shrimps. In addition, it is worth mentioning that the ratios of SMZ and TMP were unusually larger than the general aim ratio.

Graphene Oxide Inhibits Antibiotic Uptake and Antibiotic Resistance Gene Propagation.

Antibiotics and antibiotic resistance genes (ARGs) in the natural environment have become substantial threats to the ecosystem and public health. Effective strategies to control antibiotics and ARG contaminations are emergent. A novel carbon nanomaterial, graphene oxide (GO), has attracted a substantial amount of attention in environmental fields. This study discovered the inhibition effects of GO on sulfamethoxazole (SMZ) uptake for bacteria and ARG transfer among microorganisms. GO promoted the penetration of SMZ from intracellular to extracellular environments by increasing the cell membrane permeability. In addition, the formation of a GO-SMZ complex reduced the uptake of SMZ in bacteria. Moreover, GO decreased the abundance of the sulI and intI genes by approximately 2-3 orders of magnitude, but the global bacterial activity was not obviously inhibited. A class I integron transfer experiment showed that the transfer frequency was up to 55-fold higher in the control than that of the GO-treated groups. Genetic methylation levels were not significant while sulI gene replication was inhibited. The biological properties of ARGs were altered due to the GO-ARG noncovalent combination, which was confirmed using multiple spectral analyses. This work suggests that GO can potentially be applied for controlling ARG contamination via inhibiting antibiotic uptake and ARG propagation.

Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis.

For treatment of multidrug-resistant tuberculosis (MDR-TB), there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for TB-HIV-coinfected patients. However, only limited data are available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate the PK parameters and in vitro PD data on the effective part of co-trimoxazole: sulfamethoxazole. In a prospective PK study in patients infected with drug-susceptible Mycobacterium tuberculosis (drug-susceptible TB patients) (age, >18), sulfamethoxazole-trimethoprim (SXT) was administered orally at a dose of 960 mg once daily. One-compartment population pharmacokinetic modeling was performed using MW\Pharm 3.81 (Mediware, Groningen, The Netherlands). The area under the concentration-time curve for the free, unbound fraction of a drug (ƒAUC)/MIC ratio and the period in which the free concentration exceeded the MIC (fT > MIC) were calculated. Twelve patients received 960 mg co-trimoxazole in addition to first-line drugs. The pharmacokinetic parameters of the population model were as follows (geometric mean ± standard deviation [SD]): metabolic clearance (CLm), 1.57 ± 3.71 liters/h; volume of distribution (V), 0.30 ± 0.05 liters · kg lean body mass(-1); drug clearance/creatinine clearance ratio (fr), 0.02 ± 0.13; gamma distribution rate constant (ktr_po), 2.18 ± 1.14; gamma distribution shape factor (n_po), 2.15 ± 0.39. The free fraction of sulfamethoxazole was 0.3, but ranged between 0.2 and 0.4. The median value of the MICs was 9.5 mg/liter (interquartile range [IQR], 4.75 to 9.5), and that of theƒAUC/MIC ratio was 14.3 (IQR, 13.0 to 17.5). The percentage of ƒT > MIC ranged between 43 and 100% of the dosing interval. The PK and PD data from this study are useful to explore a future dosing regimen of co-trimoxazole for MDR-TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01832987.).

Variations in the fate and biological effects of sulfamethoxazole, norfloxacin and doxycycline in different vegetable-soil systems following manure application.

The fate of sulfamethoxazole (SMZ), norfloxacin (NOR) and doxycycline (DOX) and their biological effects in radish and pakchoi culture systems were investigated. DOX dissipated more rapidly than SMZ and NOR, while radish and pakchoi cultivation increased the removal of residual DOX in soils. Dissipation of NOR was accelerated in radish soils but was slowed down slightly in pakchoi soils. Vegetable cultivation exerted an insignificant effect on SMZ removal. Investigation of antibiotic bioaccumulation showed that the uptake of DOX by radish and pakchoi was undetectable, but the radish accumulated more SMZ and NOR than pakchoi. Among the three antibiotics, only SMZ use exhibited an apparent suspension of plant seed germination, up-ground plant growth and soil microbial diversity. Pakchoi responded more sensitively to SMZ than did the radish. Principal component analysis (PCA) based on MicroRESP™ indicated that the sampling time and antibiotic treatments could influence the soil microbial community. Only in the pakchoi soils did antibiotic application exert a more robust effect on the microbial community than the sampling time; SMZ treatments and DOX treatments could be clearly discriminated from the control treatments. These results are crucial for an assessment of the potential risks of antibiotics to culture system practices and suggest that good agricultural practices help to limit or even reduce antibiotic pollution.

Use of the Flory-Huggins theory to predict the solubility of nifedipine and sulfamethoxazole in the triblock, graft copolymer Soluplus.

CONTEXT: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility. OBJECTIVE: Use the Flory-Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution. MATERIALS AND METHODS: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory-Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug-polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (Tg) curves. RESULTS: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and Tg curves in the phase diagram. DISCUSSION: Negative interaction parameters indicated strong drug-polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting. CONCLUSION: The Flory-Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.

Removal of pharmaceutically active compounds (PhACs) and toxicological response of Cyperus alternifolius exposed to PhACs in microcosm constructed wetlands.

This study investigated the effects of selected four pharmaceutically active compounds (PhACs) (carbamazepine, sulfamethoxazole, ofloxacin, and roxithromycin) on the photosynthesis and antioxidant enzymes of Cyperus alternifolius in constructed wetlands (CWs). Moreover, the removal and kinetics of PhACs in CWs were evaluated to explore the related removal mechanisms. Results showed that C. alternifolius can uptake and withstand certain PhACs. The PhAC tolerance of C. alternifolius might be attributed to their capacity to maintain relatively normal photosynthetic activity and elevated antioxidative defense. CWs offered comparable or even higher removal efficiencies for the selected PhACs compared with conventional WWTPs. The removal of the target PhACs was enhanced in the planted CWs versus the unplanted CWs mostly because of plant uptake and rhizosphere effects. In particular, carbamazepine, which is considered the most recalcitrant of the PhACs, was significantly reduced (p<0.05). The removal of target PhACs fitted into two distinct periods. The initial fast step (within the first 2 h) was essentially attributed to the adsorption onto the CW medium surface. The subsequent slow process (2-12 h) closely followed first-order kinetics probably because of the interaction between microorganisms and plants. The obtained results indicate that C. alternifolius can phytoremediate PhAC-contaminated waters in CWs.

Quantitative assessment of the effects of sulfamethoxazole on Toxoplasma gondii loads in susceptible WT C57BL/6 mice as an immunocompetent host model.

The abundance of Toxoplasma gondii with or without sulfamethoxazole (SMX) treatment was evaluated with quantitative competitive polymerase chain reaction in various organs of wild-type C57BL/6 mice, a susceptible immunocompetent host, after peroral infection with a cyst-forming Fukaya strain of T. gondii. SMX affected different organs in three ways: T. gondii was reduced independently of SMX (skin and kidney); T. gondii was not eradicated with continuous treatment (brain, heart, and lung); and T. gondii was eradicated with continuous treatment (tongue, skeletal muscle, and small intestine). The SMX concentrations in the brains, hearts, and lungs were higher in infected mice than in uninfected mice. These results indicate that even in an immunocompetent host, chemotherapy is necessary to reduce the parasite load and thus reduce the risk of recurrent disease.

Structural characterization of new Schiff bases of sulfamethoxazole and sulfathiazole, their antibacterial activity and docking computation with DHPS protein structure.

New Schiff bases (1, 2) of substituted salicylaldehydes and sulfamethoxazole (SMX)/sulfathiazole (STZ) are synthesized and characterized by elemental analysis and spectroscopic data. Single crystal X-ray structure of one of the compounds (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (1c) has been determined. Antimicrobial activities of the Schiff bases and parent sulfonamides (SMX, STZ) have been examined against several Gram-positive and Gram-negative bacteria and sulfonamide resistant pathogens; the lowest MIC is observed for (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-N-(thiazol-2-yl)benzene sulfonamide (2c) (8.0 µg mL(-1)) and (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-N-(5-methylisoxazol-3-yl)benzene sulfonamide (1c) (16.0 µg mL(-1)) against sulfonamide resistant pathogens. DFT optimized structures of the Schiff bases have been used to carry out molecular docking studies with DHPS (dihydropteroate synthase) protein structure (downloaded from Protein Data Bank) using Discovery Studio 3.5 to find the most preferred binding mode of the ligand inside the protein cavity. The theoretical data have been well correlated with the experimental results. Cell viability assay and ADMET studies predict that 1c and 2c have good drug like characters.

Biological uptake and depuration of sulfadiazine and sulfamethoxazole in common carp (Cyprinus carpio).

Sulfonamides, a class of the most commonly used antibiotics, are being increasingly released into the aquatic environment and have recently caused considerable concerns. However, knowledge on their fate and ecotoxicological effects upon aquatic organisms is not understood yet. This work investigated mainly the bioconcentration kinetics (uptake/depuration) of sulfadiazine (SDZ) and sulfamethoxazole (SMZ) in common carp (Cyprinus carpio) by exposure in different concentrations under semi-static conditions for 48 d. The uptake rate (k1), growth-corrected depuration rate (k 2g), and biological half-lives (t1/2) of two sulfonamides in liver and muscle were determined and they were 0.135-9.84 L kg(-1)d(-1), 0.0361-0.838 d(-1), 8.3-19.2d, respectively. With exposure concentrations increasing, the uptake rates in liver and muscle decreased obviously but the depuration rates were not closely related with the exposure concentrations. SDZ exhibited higher uptake but lower excretion rates in almost all the liver and muscle than SMZ, resulting in both higher BCFs and half-lives for SDZ. The growth-corrected bioconcentration factors (BCF kg) were measured to be 1.65-165.73 L kg(-1)ww and their averages were in good consistency with the values predicted by previous models within one log unit. The work presented here was the first to model bioconcentration of SMZ and SDZ from water by laboratory-exposed fish.

Profiling the physiological and molecular response to sulfonamidic drug in Procambarus clarkii.

Sulfamethoxazole (SMZ) is one of the most widely employed sulfonamides. Because of the widespread use of SMZ, a considerable amount is indeed expected to be introduced into the environment. The cytotoxicity of SMZ relies mainly on arylhydroxylamine metabolites (S-NOH) of SMZ and it is associated with the production of reactive oxygen species (ROS). There is limited information about the toxic potential of SMZ at the cellular and molecular levels, especially in aquatic and/or non-target organisms. In the present study, the red swamp crayfish (Procambarus clarkii), being tolerant to extreme environmental conditions and resistant to disease, was used as a model organism to profile the molecular and physiological response to SMZ. Haemolymphatic-immunological parameters such as glucose serum levels and total haemocyte counts were altered; moreover, a significant increase in Hsp70 plasma levels was detected for the first time. Variations at the transcriptional level of proinflammatory genes (cyclooxygenase-1, COX 1, and cyclooxygenase-2, COX 2), antioxidant enzymes (glutathione-S-transferase, GST and manganese superoxide dismutase MnSOD), stress response and Fenton reaction inhibitor genes (heat-shock protein 70 HSP70, metallothionein, MT and ferritin, FT) were evaluated, and alterations in the canonical gene expression patterns emerged. Considering these results, specific mechanisms involved in maintaining physiological homeostasis and adaptation in response to perturbations are suggested.

Effect of MMX® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials.

BACKGROUND: MMX(®) mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections. AIM: To evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies. METHODS: In all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1-4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1-3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1-3 and once on day 4 (N=44). RESULTS: MMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) fell within the predefined equivalence range (0.80-1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild. CONCLUSION: MMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics. CLINICALTRIALSGOV IDENTIFIERS: NCT01442688, NCT01402947, NCT01418365, and NCT01469637.

Dissolution rate enhancement, in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions.

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions.

Pharmacokinetic study of a new derivative of sulfamethoxazole.

The study was aimed at determination of pharmacokinetic parameters of a previously synthesized salicylidine-sulfamethoxazole-Zn(II) monohydrate in normal humans. This new derivative of sulfamethoxazole was reported to be more active and less toxic than the parent drug by our group. 10 volunteers received a 200 mg dose of the drug orally. Blood samples were collected just before and after 0.16, 0.33, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0 and 8.0 h of administration of the drug. The plasma samples were analyzed for sulfamethoxazole by a new validated high performance liquid chromatography method having a suitable limit of quantification. The dose of each drug was well tolerated without any adverse effect. The maximum plasma sulfamethoxazole concentration was 280 µg L - 1 at a tmax 1.30 h. This suggests a rapid onset effect of the complex as compared with the parent drug. The plasma half-life, clearance, and volume of distribution of sulfamethoxazole from salicylidine-sulfamethoxazole-Zn(II) monohydrate were 1.64 h, 0.24 L h - 1 and 0.57 L kg - 1 respectively. The elimination of sulfamethoxazole followed the first order kinetics with R2>0.984. The larger value of volume of distribution and clearance for the new derivative, as compared to that of the parent drug, show that the new derivative may exhibit prolonged antimicrobial effect with rapid clearance.

Comparison of the pharmacokinetics of sulfamethoxazole in native Han and Tibetan male Chinese volunteers living at high altitude.

The aim of this study was to investigate the pharmacokinetics of sulfamethoxazole in native Han and Tibetan healthy Chinese subjects living chronically at high altitude. An open-labeled, controlled, prospective study was conducted in healthy Chinese male volunteers. Sulfamethoxazole 1,200 mg was administered orally to two groups: native Han and Tibetan volunteers living at high altitude (2,500-3,900 m [8,200-12,800 ft]). Blood samples were collected from an indwelling venous catheter into heparinized tubes before (baseline) study drug administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 h after study drug administration. Sulfamethoxazole in whole blood, plasma, and plasma water, and metabolite N (4)-acetyl-sulfamethoxazole in plasma were determined by HPLC. Tolerability was determined using blood chemistry testing, continuous 12-lead electrocardiogram, and blood pressure monitoring. The protein binding was significantly higher in the native Tibetan group (70.5 %) compared to the native Han group (67.3 %) (p < 0.05). The binding of sulfamethoxazole to red blood cells was 7.4 and 8.3 % in the native Han and native Tibetan groups, respectively. There was no significant difference between the two groups. The AUC(0-∞) was significantly lower in the native Tibetan group compared to the native Han group (p < 0.05), and other pharmacokinetics parameters were found to have no significant difference between the two groups. This study found little changes in the disposition of sulfamethoxazole in these native healthy Tibetan Chinese subjects living at high altitude in comparison to native healthy Han Chinese subjects living at high altitude.

Influence of NAT2 polymorphisms on sulfamethoxazole pharmacokinetics in renal transplant recipients.

The sulfamethoxazole (SMX)-trimethoprim drug combination is routinely used as prophylaxis against Pneumocystis pneumonia during the first 3 to 6 months after renal transplantation. The objective of this study was to examine the impact of N-acetyltransferase 2 (NAT2) and CYP2C9 polymorphisms on the pharmacokinetics of SMX in 118 renal transplant recipients. Starting on day 14 after renal transplantation, patients were administered 400 mg/day-80 mg/day of SMX-trimethoprim orally once daily. On day 14 after the beginning of SMX therapy, plasma SMX concentrations were determined by a high-performance liquid chromatography method. The SMX area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for 15 recipients with the NAT2 slow acetylator genotype (NAT2 5/ 6, - 6/ 6, - 6/ 7, and - 7/ 7) was significantly greater than that for 56 recipients with the NAT2 rapid acetylator genotype (homozygous for NAT2 4) (766.4 ± 432.3 versus 537.2 ± 257.5 µg-h/ml, respectively; P = 0.0430), whereas there were no significant differences in the SMX AUC(0-24) between the CYP2C9 1/ 1 and - 1/ 3 groups. In a multiple regression analysis, the SMX AUC(0-24) was associated with NAT2 slow acetylator polymorphisms (P = 0.0095) and with creatinine clearance (P = 0.0499). Hepatic dysfunction in NAT2 slow acetylator recipient patients during the 6-month period after SMX administration was not observed. SMX plasma concentrations were affected by NAT2 polymorphisms and renal dysfunction. Although standard SMX administration to patients with NAT2 slow acetylator polymorphisms should be accompanied by monitoring for side effects and drug interaction effects from the inhibition of CYP2C9, SMX administration at a low dose (400 mg) as prophylaxis may not provide drug concentrations that reach the level necessary for the expression of side effects. Further studies with a larger sample size should be able to clarify the relationship between SMX plasma concentration and side effects.