[Establishment and application of a nomogram model for prognostic risk prediction in patients with epithelial ovarian cancer].

Objective: To explore the prognostic factors of epithelial ovarian carcinoma (EOC), construct a nomogram model, and evaluate the prognosis of EOC patients. Methods: A retrospective analysis was performed on clinicopathological data of 208 cases of EOC patients who received initial treatment in the First Affiliated Hospital of Army Medical University from August 11, 2016 to July 11, 2018, including age, preoperative ascites, preoperative neoadjuvant chemotherapy, surgical method, pathological type, pathological differentiation degree, surgical pathology stage, preoperative and post-chemotherapy serum cancer antigen 125 (CA125) level, human epididymal protein 4 (HE4) level, platelet count and platelet/lymphocyte number ratio (PLR). The univariate and multivariate Cox risk ratio models were used to analyze the related factors affecting progression free survival (PFS) in EOC patients, and the prediction nomogram of PFS in EOC patients was established to evaluate its efficacy in predicting PFS. Results: Univariate analysis showed that preoperative neoadjuvant chemotherapy, pathological type, pathological differentiation degree, surgical pathology stage, serum CA125 and HE4 level before operation and after chemotherapy, platelet count and PLR before operation and after chemotherapy were significantly correlated with PFS in EOC patients (all P<0.05). Multivariate analysis showed that surgical pathology stage, preoperative PLR, serum CA125 and HE4 level after chemotherapy were independent prognostic factors affecting PFS of EOC patients (all P<0.01). The index coefficient of the prediction model for the prognosis of EOC patients established by this method was 0.749 (95% CI: 0.699-0.798), which had good prediction ability, and could help clinicians to more accurately evaluate the prognosis of EOC patients. Conclusion: The nomogram model constructed based on surgical pathology stage, preoperative PLR, serum CA125 and HE4 level after chemotherapy could effectively predict the PFS of EOC patients after initial treatment, could help clinicians to screen high-risk patients, provide individualized treatment, and improve the prognosis of EOC patients.

Genotype replacement within serotype 23F Streptococcus pneumoniae in Beijing, China: characterization of serotype 23F.

We investigated the genetic structure of 99 isolates of serotype 23F Streptococcus pneumoniae from children with acute respiratory infections collected over two periods from 1997 to 2006, and 2010. All isolates were susceptible to vancomycin and amoxicillin-clavulanic acid; 97 were resistant to erythromycin, 95 of which carried the ermB gene and two carried both mefA/E and ermB genes. Multidrug resistance to three or more classes of antibiotics was exhibited by 90 isolates. Sequence types ST342 and ST81 were the most frequent in 1997-2006 and 2010, respectively. All CC81 isolates were non-susceptible to ß-lactam antibiotics and had higher minimum inhibitory concentration values for penicillin than other clone complexes and sequence types. The increased ß-lactam antibiotic resistance may have resulted from the replacement of multidrug-resistant clones related to ST81. Long-term studies on S. pneumoniae serotype 23F, especially the ST81 clone, should be conducted to better understand the epidemiological picture of this pathogen in China.

Spread of multidrug-resistant clonal complex 271 of serotype 19F Streptococcus pneumoniae in Beijing, China: characterization of serotype 19F.

We investigated the genetic structure of 120 isolates of serotype 19F Streptococcus pneumoniae from Chinese children with acute respiratory infections collected from 1997 to 2006, and 2010. All strains were susceptible to vancomycin and levofloxacin, and only five strains were not susceptible to penicillin. The non-susceptibility rate to cephalosporins increased from 1997 to 2010. Of 119 erythromycin-resistant strains, 60 carried both ermB and mefA genes. The percentage of clonal complex 271 (CC271) increased from 14.3% in 1997-1998 to 92% in 2010, whereas that of CC983 decreased from 64.3% to 0%. CC271 had a higher non-susceptibility rate to ß-lactam antibiotics than CC983 and other CCs. The increased non-susceptibility rate to ß-lactam antibiotics in serotype 19F pneumococci was found to be associated with the spread of the international resistant clone CC271 presumably caused by antibiotic pressure. Long-term surveys of serotype 19F S. pneumoniae are required to monitor CC prevalence and trends in antimicrobial resistance.

Bionic dental pulp: its potential value following root canal therapy.

Dental pulp can provide nutrition for teeth. The teeth after root canal therapy without pulp will turn frailer because of dehydration, and it may be easily broken. Bionic dental pulp possesses similar components of the healthy dental pulp. So we put forward a hypothesis that bionic dental pulp can be filled into root canals to provide nutrition for teeth like healthy pulp. Then the life-span of teeth after root canal therapy could increase.

Environmental and health effects of the herbicide glyphosate.

The herbicide glyphosate, N-(phosphonomethyl) glycine, has been used extensively in the past 40years, under the assumption that side effects were minimal. However, in recent years, concerns have increased worldwide about the potential wide ranging direct and indirect health effects of the large scale use of glyphosate. In 2015, the World Health Organization reclassified glyphosate as probably carcinogenic to humans. A detailed overview is given of the scientific literature on the movement and residues of glyphosate and its breakdown product aminomethyl phosphonic acid (AMPA) in soil and water, their toxicity to macro- and microorganisms, their effects on microbial compositions and potential indirect effects on plant, animal and human health. Although the acute toxic effects of glyphosate and AMPA on mammals are low, there are animal data raising the possibility of health effects associated with chronic, ultra-low doses related to accumulation of these compounds in the environment. Intensive glyphosate use has led to the selection of glyphosate-resistant weeds and microorganisms. Shifts in microbial compositions due to selective pressure by glyphosate may have contributed to the proliferation of plant and animal pathogens. Research on a link between glyphosate and antibiotic resistance is still scarce but we hypothesize that the selection pressure for glyphosate-resistance in bacteria could lead to shifts in microbiome composition and increases in antibiotic resistance to clinically important antimicrobial agents. We recommend interdisciplinary research on the associations between low level chronic glyphosate exposure, distortions in microbial communities, expansion of antibiotic resistance and the emergence of animal, human and plant diseases. Independent research is needed to revisit the tolerance thresholds for glyphosate residues in water, food and animal feed taking all possible health risks into account.

Modeling transport and fate of nitrogen from urea applied to a near-trench paddy field.

A simple but comprehensive model is developed to quantify N losses from urea applied to a near-trench paddy field, considering all the N-transformations such as urea hydrolysis, volatilization, nitrification, denitrification, and all the important transportations like runoff, lateral seepage, vertical leaching and crop uptake. Seasonal average data of field observations for three crop seasons were used for model calibration and validation, which showed that ammonia volatilization accounted for 26.5-29.4% of the applied N and N uptake by crop occupied 38.2-44.8%, while N losses via surface runoff, vertical leaching and lateral seepage varied from 5.6-7.7%, 4.0-4.9% to 5.0-5.3% of the applied N, respectively. These observed results were well predicted by our model, indicating that the model performed effectively at quantifying N losses via individual processes in a wide range of urea application rates and benefit for developing water and fertilizer management strategies for near-trench paddy fields.

Expression of corticotrophin-releasing hormone and its receptor in patients with intrahepatic cholestasis of pregnancy.

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disorders. Although various biological effects of corticotrophin-releasing hormone (CRH) has in pregnancy have been reported, its activities in patients with ICP are lacking. Here we evaluated CRH and its receptor (CRH-R1) expression in placenta and serum in control and ICP patients, to assess their potential activities in the ICP pathogenesis. METHODS AND MATERIALS: Placental tissues were obtained from the control and ICP patients (10 cases for each group) between 37 and 39 gestational weeks. Immunohistochemistry, Western Blotting and real-time PCR analysis were used to detect the CRH and CRH-R1 expression in placenta. Meanwhile, maternal serums were analyzed for detecting CRH in the control and ICP patients (80 cases for each group) in 34-37 gestational weeks. All data were observed and recorded for comparing and analyzing in control and ICP patients. RESULTS: CRH staining was found in syncytiotrophoblast and feto-placental vascular endothelium cells of placenta, whereas CRH-R1 staining was found in syncytiotrophoblast by using immunohistochemical analysis. The CRH expression level in ICP placenta was significantly lower than those results in controls (P < 0.01). For CRH-R1, CRH mRNA and CRH-R1 mRNA expressions, no statistical differences were found between control and ICP groups (all P > 0.05). Serum CRH levels increased in both control and ICP groups, but the growth rate was limited in ICP group, especially in late pregnancy (P < 0.05). CONCLUSIONS: The down-regulation of CRH in ICP placentas and the limited growth rate of CRH in the maternal serum of ICP patients might impair the blood flow regulation of the utero-placental-fetal unit, which might result in poor fetoplacental vascular perfusion and adverse pregnancy outcomes. CRH might play a significant role in the pathogenesis of ICP and provide a new approach to further investigate the etiology of ICP.

Application of (15)N- (18)O double stable isotope tracer technique in an agricultural nonpoint polluted river of the Yangtze Delta Region.

One strategy to combat nitrate (NO3-N) contamination in rivers is to understand its sources. NO3-N sources in the East Tiaoxi River of the Yangtze Delta Region were investigated by applying a (15)N-(18)O dual isotope approach. Water samples were collected from the main channel and from the tributaries. Results show that high total N and NO3-N are present in both the main channel and the major tributaries, and NO3-N was one of the most important N forms in water. Analysis of isotopic compositions (δ (18)O, δD) of water suggests that the river water mainly originated from three tributaries during the sampling period. There was a wide range of δ (15)N-NO3 (-1.4 to 12.4 ‰) and a narrow range of δ (18)O-NO3 (3.7 to 9.0 ‰) in the main channel waters. The δ (15)N and δ (18)O-NO3 values in the upper, middle, and lower channels along the river were shifted as 8.2, 3.5, and 9.5 ‰, and 9.0, 4.2, and 6.0 ‰, respectively. In the tributary South Tiao, the δ (15)N and δ (18)O-NO3 values were as high as 9.5 and 7.0 ‰, while in the tributaries Mid Tiao and North Tiao, NO3-N in most of the samples had relatively low δ (15)N and δ (18)O-NO3 values from 2.3 to 7.5 ‰ and 4.7 to 7.0 ‰, separately. Our results also suggest that the dual isotope approach can help us develop the best management practice for relieving NO3-N pollution in the rivers at the tributary scale.

Bionic restorative system: its potential value in caries therapy.

Dental defect caused by dental caries is usually restored by fillings, inlays or onlays at the present day. Although the therapeutic effects of these methods have already been confirmed, complications occasionally set in, such as pulp injury, fracture and secondary caries. Bionic dental organic center possesses similar functions of the natural dental organic center. So we put forward a hypothesis that bionic organic center can be transplanted onto the conditioned pulpal walls of the prepared cavity and a specific filling material, which the cavity will be filled with, provides oxygen, nutrition and raw materials for it to regenerate the lost odontal tissue in vivo. The regenerated odontal tissue which has similar properties of the healthy odontal tissue will restore the defect and it will be combined with the residual odontal tissue tightly, not only in physical structure but also in function. Then the teeth suffering from dental caries could live and function like healthy ones.

Metabolism and disposition of a beta 3-adrenergic receptor agonist LY 368842 in male Fisher 344 rats.

The metabolism and disposition of LY 368842, a beta 3-adrenergic receptor agonist, were characterized in F344 rats following oral or intravenous administration of [(14)C]LY 368842. These studies were conducted as part of the investigation of the mechanism of dark liver pigmentation in LY 368842-treated F344 rats. The maximum plasma concentration of LY 368842 was reached at 3 h after an oral dose, with an elimination half-life of 4 h. The oral bioavailability of LY 368842 was determined as 8%. A tissue distribution study by quantitative whole-body autoradiography indicated high concentrations of radiocarbon in gastrointestinal contents and moderate concentrations in liver. The radiocarbon was rapidly eliminated in rats, with approximately 3% of the dose recovered in urine and 90% in faeces over 168 h. In bile duct-cannulated rats, about 42% of the dose was recovered in bile and 41% remained in the faeces. Metabolites of LY 368842 were identified in rat urine, faeces, bile and plasma samples. Oxidative metabolism of LY 368842 led to the formation of a hydroxy metabolite, an indole-2,3-dione metabolite and oxidative cleavage products such as amine and diol metabolites. Several glucuronide conjugates were also identified in rat bile. These data suggest that LY 368842 is not completely absorbed but is widely distributed, extensively metabolized and rapidly eliminated in rats after oral administration.

Interaction between residues Glu269 (helix VIII) and His322 (helix X) of the lactose permease of Escherichia coli is essential for substrate binding.

Site-directed and Cys-scanning mutagenesis of the lactose permease of Escherichia coli reveals that as few as four residues--Glu269 (helix VIII), Arg302 (helix IV), His322 (helix X), and Glu325 (helix X)--are irreplaceable for coupling substrate and H+ translocation. Interestingly, the four residues are in close physical proximity, Glu269 interacting with His322 and Arg302 with Glu325. In addition, the substrate translocation pathway is located close to the four residues at the interface between helices V and VIII. To investigate the importance of the four residues and their interactions for substrate binding, mutation Glu269-->Asp, Glu269-->Gln, Arg302-->Ala, Arg302-->Lys, His322-->Ala, His322-->Phe, Glu325-->Asp, or Glu325-->Gln was introduced into single-Cys148 permease, where the reactivity of Cys with 2-(4-maleimidoanilino)naphthalene-6-sulfonic acid (MIANS) is blocked by binding of substrate. The double mutants were purified, and the rates of MIANS labeling were measured in the absence or presence of beta-D-galactopyranosyl 1-thio-beta-D-galactopyranoside (TDG), lactose, or galactose at various concentrations. Remarkably, substrate binding by the Glu269 or His322 mutants is abolished or decreased dramatically, while binding by the Arg302 or Glu325 mutants is not altered. The observations are consistent with the notion that the interaction between Glu269 and His322 stabilizes the interface between helices V and VIII and thereby leads to binding of substrate.

In vitro folding of a membrane protein: effect of denaturation and renaturation on substrate binding by the lactose permease of Escherichia coli.

Site-directed mutagenesis and site-directed fluorescence spectroscopy demonstrate that Cys148 interacts hydrophobically with the galactosyl moiety of substrates of the lactose permease of Escherichia coli. By taking advantage of the finding that labelling of single-Cys148 permease with the thiol-specific fluorophore 2-(4'-maleimidylanilino)naphthalene-6-sulfonic acid (MIANS) is blocked specifically by substrates of the permease, it is demonstrated that the high-affinity ligand beta,D-galactopyranosyl 1-thio-beta,D-galactopyranoside (TDG) stabilizes solubilized, purified permease against heat denaturation. Furthermore, TDG protection against MIANS labelling of single-Cys148 permease is abolished by guanidinium hydrochloride. After dialysis of the denaturant, TDG protection against MIANS labelling is recovered, indicating that the permease has been refolded. The conclusion is confirmed and extended by studying site-directed fluorescence of purified single-Cys331 permease, where the emission spectrum of the MIANS-labelled protein is differentially altered by low or high concentrations of TDG. The results demonstrate that both low- and high-affinity binding, as well as ligand-induced conformational changes in the permease, can be denatured reversibly in vitro.

Cysteine-scanning mutagenesis of transmembrane domain XII and the flanking periplasmic loop in the lactose permease of EScherichia coli.

Using a functional lactose permease mutant devoid of Cys residues (C-less permease), each amino acid residue in transmembrane domain XII and the periplasmic loop between putative helices XI and XII (loop XI/XII) was replaced individually with Cys. Out of 34 mutants, 31 exhibit 60-100% or more of C-less activity, mutants Gly377-->Cys and Leu385-->Cys exhibit lower rates of transport but accumulate lactose about 60-70% as well as C-less, and mutant Leu400-->Cys exhibits < 20% of C-less activity. Immunoblots reveal that all of the mutant proteins are present in the membrane in amounts comparable to that of C-less with the exception of mutants Gly377-->Cys and Leu385-->Cys which are expressed about 40% as well as C-less and mutant Leu400-->Cys which is hardly detectable. When transferred to the wild-type background, however, mutant Leu400-->Cys is expressed normally and exhibits highly significant transport activity. Finally, each active Cys-replacement mutant was assayed for sensitivity to N-ethylmaleimide, and with three exceptions, the mutants are essentially unaffected by the alkylating agent. Mutants Val367-->Cys, Gly370-->Cys, and Tyr373-->Cys which are predicted to be immediately distal to helix XI in loop XI/XII are significantly inactivated. The periodicity observed suggests that the periplasmic end of transmembrane domain XI may extend to position 373. In the following paper [Voss, J., He, M. M., Hubbell, W. L., & Kaback, H. R. (1996) Biochemistry 35, 12915-12918], site-directed spin labeling of single-Cys mutants at positions 387-402 is used to demonstrate that transmembrane domain XII is in an alpha-helical conformation.

Use of designed metal-binding sites to study helix proximity in the lactose permease of Escherichia coli. 1. Proximity of helix VII (Asp237 and Asp240) with helices X (Lys319) and XI (Lys358).

The lactose permease of Escherichia coli contains two pairs of oppositely charged residues that interact functionally, Asp240 (helix VII)/Lys319 (helix X) and Asp237 (helix VII)/Lys358 (helix XI). Single- and double-His replacement mutants at these positions have been constructed and characterized with respect to transport activity and Mn2+ binding. The following results confirm the functional interactions between both sets of residues: (i) At pH 7.5, where the imidazole is likely to be unprotonated, the double-His mutants Asp237 --> His/Lys358 --> His and Asp240 --> His/Lys319 --> His exhibit significant transport activity while the single-His mutants Lys319 --> His and Lys358 --> His are inactive. (ii) At pH 5.5, where the imidazole is likely to be protonated, the double-His mutants Asp240 --> His/Lys319 --> His and Asp237 --> His/Lys358 --> His are inactive; however, the single-His mutant Lys319 --> His exhibits significant activity. (iii) The single-His mutant Asp237 --> His or ASP240 --> His is inactive at all pH values tested. In addition, a pH titration of Asp237 --> His/Lys358 --> His permease activity exhibits a midpoint at about 6.2. Finally, the purified mutant proteins Asp237 --> His/Lys358 --> His and Asp240 --> His/Lys319 --> His were assayed for Mn2+ binding by electron paramagnetic resonance spectroscopy. Asp237 --> His/Lys358 --> His permease binds Mn2+ with a stoichiometry of unity at pH 7.5, but much less binding is observed at pH 5.5, demonstrating directly that helix VII (Asp237) is in close proximity to helix XI (Lys358).(ABSTRACT TRUNCATED AT 250 WORDS)

Use of designed metal-binding sites to study helix proximity in the lactose permease of Escherichia coli. 2. Proximity of helix IX (Arg302) with helix X (His322 and Glu325).

Engineering divalent metal-binding sites into the lactose permease of Escherichia coli by introducing bis-His residues has been utilized to confirm the proximity of helices VIII (Glu269 --> His) and X (His322) [Jung, K., Voss, J., He, M., Hubbell, W. L., & Kaback, H. R. (1995) Biochemistry 34, 6272] and helices VII (Asp237 --> His) and XI (Lys358 --> His) [He, M. M., Voss, J., Hubbell, W. L., & Kaback, H.R. (1995) Biochemistry 34, 00000--00000]. In this paper, the approach is used to confirm and extend the relationship between helices IX (Arg302) and X (His322 and Glu325) [Jung, K., Jung, H., Wu, J., Prive, G. G., l& Kaback, H. R. (1993) Biochemistry 32, 12273]. Thus, mutants Arg302 --> His, Glu325 --> His, and Arg302 --> His/Glu325 --> His were constructed, and Mn2+ binding was assayed by electron paramagnetic resonance. Mutant Arg302 --> His binds Mn2+ with a KD of about 24 microM and a stoichiometry approximating unity in all likelihood because the His residue at position 302 forms a metal-binding site in conjunction with the native His residue at position 322. Mutant Arg302 --> His/Glu325 --> His also binds Mn2+ with a 1:1 stoichiometry, but the KD is decreased to about 13 microM. The results suggest that Arg302 is sufficiently close to both Glu325 and His322 to form a tridentate metal-binding site in mutant Arg302 --> His/Glu325 --> His. In contrast, replacement of Glu325 with His in permease with a native His residue at position 322 does not lead to Mn2+ binding. The results provide strong support for the helix packing model proposed.

Arginine 302 (helix IX) in the lactose permease of Escherichia coli is in close proximity to glutamate 269 (helix VIII) as well as glutamate 325.

By using a variety of biochemical and biophysical approaches, a helix packing model for the lactose permease of Escherichia coli has been proposed in which the four residues that are irreplaceable with respect to coupling are paired--Glu269 (helix VIII) with His322 (helix X) and Arg302 (helix XI) with Glu325 (helix X). In addition, the substrate translocation pathway is located at the interface between helices V and VIII, which is in close vicinity to the four essential residues. Based on this structural information and functional studies of mutants in the four irreplaceable residues, a molecular mechanism for energy coupling in the permease has been proposed [Kaback, H. R. (1997) Pro.c Natl. Acad. Sci. U.S.A. 94, 5539]. The principle idea of this model is that Arg302 interacts with either Glu325 or Glu269 during turnover. Evidence that Arg302 is in close proximity with Glu325 has been presented [Jung, K., Jung, H., Wu, J., Prive, G. G., & Kaback, H. R. (1993) Biochemistry 32, 12273; He, M. M., Voss, J., Hubbell, W. L., & Kaback, H. R. (1995) Biochemistry 34, 15667]; however, the proximity of Arg302 to Glu269 has not been examined. In this report, it is shown by two methods that Arg302 is also close to Glu269: (i) permease with Glu269-->His, Arg302-->His, and His322-->Phe binds Mn2+ with high affinity at pH 7.5, but not at pH 5.5; and (ii) site-directed spin-labeling of the double Cys mutant Glu269-->Cys/Arg302-->Cys exhibits spin-spin interaction with an interspin distance of about 14-16 A. In addition, the spin-spin interaction is stronger and interspin distance shorter after the permease is reconstituted into proteoliposomes. Taken as a whole, the data are consistent with the idea that Arg302 may interact with either Glu325 or Glu269 during turnover.

Site-directed spin labeling demonstrates that transmembrane domain XII in the lactose permease of Escherichia coli is an alpha-helix.

Functional lactose permease mutants containing single-Cys residues at positions 387-402 [He, M. M., Sun, J., & Kaback, H. R. (1996) Biochemistry 35, 12909-12914] and a biotin acceptor domain in the middle cytoplasmic loop were solubilized in n-dodecyl-beta-D-maltopyranoside and purified by avidin affinity chromatography. Each mutant protein was derivatized with a thiol-selective nitroxide reagent and examined by conventional and power saturation electron paramagnetic resonance spectroscopy. Analysis of the electron paramagnetic resonance spectral line shapes and the influence of O2 on the saturation behavior of the spin-labeled proteins were measured in order to obtain information on the mobility of the spin-labeled side chains and their accessibility to O2, respectively. The data show a periodic dependence of both mobility and accessibility on sequence position consistent with an alpha-helical structure. These results provide direct support for the contention that transmembrane domain XII is in an alpha-helical conformation and on the periphery of the 12-helix bundle that comprises the lactose permease molecule.

Determination of the structure of Escherichia coli glyoxalase I suggests a structural basis for differential metal activation.

The metalloenzyme glyoxalase I (GlxI) converts the nonenzymatically produced hemimercaptal of cytotoxic methylglyoxal and glutathione to nontoxic S-D-lactoylglutathione. Human GlxI, for which the structure is known, is active in the presence of Zn(2+). Unexpectedly, the Escherichia coli enzyme is inactive in the presence of Zn(2+) and is maximally active with Ni(2+). To understand this difference in metal activation and also to obtain a representative of the bacterial enzymes, the structure of E. coli Ni(2+)-GlxI has been determined. Structures have also been determined for the apo enzyme as well as complexes with Co(2+), Cd(2+), and Zn(2+). It is found that each of the protein-metal complexes that is catalytically active has octahedral geometry. This includes the complexes of the E. coli enzyme with Ni(2+), Co(2+), and Cd(2+), as well as the structures reported for the human Zn(2+) enzyme. Conversely, the complex of the E. coli enzyme with Zn(2+) has trigonal bipyramidal coordination and is inactive. This mode of coordination includes four protein ligands plus a single water molecule. In contrast, the coordination in the active forms of the enzyme includes two water molecules bound to the metal ion, suggesting that this may be a key feature of the catalytic mechanism. A comparison of the human and E. coli enzymes suggests that there are differences between the active sites that might be exploited for therapeutic use.

Metabolism and disposition of moxonidine in Fischer 344 rats.

The metabolism and disposition of moxonidine (4-chloro-5-(imidazolidin-2-ylidenimino)-6-methoxy-2-methylp yrimidine ), a potent central-acting antihypertensive agent, were investigated in F344 rats. After an i.v. or oral administration of 0.3 mg/kg of [(14)C]moxonidine, the maximum plasma concentrations of moxonidine were determined to be 146.0 and 4.0 ng/ml, respectively, and the elimination half-lives were 0.9 and 1.1 h, respectively. The oral bioavailability of moxonidine was determined to be 5.1%. The metabolic and elimination profiles of moxonidine were determined after an oral administration of 5 mg/kg of [(14)C]moxonidine. More than fifteen phase I and phase II metabolites of moxonidine were identified in the different biological matrices (urine, plasma, and bile). Oxidative metabolism of moxonidine leads to the formation of hydroxymethyl moxonidine and a carboxylic acid metabolite as the major metabolites. Several GSH conjugates, cysteinylglycine conjugates, cysteine conjugates, and a glucuronide conjugate were also identified in rat bile samples. The radiocarbon was eliminated primarily by urinary excretion in rats, with 59.5% of total radioactivity recovered in the urine and 38.4% recovered in the feces within 120 h. In bile duct-cannulated rats, about 39.7% of the radiolabeled dose was excreted in the urine, 32.6% excreted in the bile, and approximately 2% remained in the feces. The results from a quantitative whole body autoradiography study indicate that radiocarbon associated with [(14)C]moxonidine and/or its metabolites was widely distributed to tissues, with the highest levels of radioactivity observed in the kidney and liver. In summary, moxonidine is well absorbed, extensively metabolized, widely distributed into tissues, and rapidly eliminated in rats after oral administration.