Pharmacokinetics and safety of injected ornidazole compared to its enantiomer levornidazole in healthy Chinese subjects.

OBJECTIVE: To compare the pharmacokinetics of levornidazole and ornidazole in healthy Chinese subjects after a single intravenous injection, and to determine whether the chiral inversion of levornidazole occurs in vivo. MATERIALS AND METHODS: The study was a randomized, open-label, two-period crossover, single-dose design. A total of 12 subjects were enrolled in this study. Subjects received an intravenous injection of either levornidazole sodium chloride injection (200 mL: 0.5 g) or ornidazole sodium chloride injection (200 mL: 0.5 g) once per period. The plasma concentrations of levornidazole, ornidazole, and their metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Phenix WinNolin software (version 6.4) was used to calculate the pharmacokinetic parameters of levornidazole, ornidazole, and their metabolites. RESULTS: Dexornidazole was not detected in the plasma or urine. After a single intravenous injection of levornidazole or ornidazole, there was no significant difference in Cmax between the two drugs (p < 0.05). The AUC0-∞ and AUC0-t of levornidazole were slightly lower than those of ornidazole. Metabolites M1 and M4 were detected in the plasma of both drugs, and their pharmacokinetic parameters were similar. Metabolites M1, M2, and M4 were present in urine. The average cumulative urinary excretion rates of levornidazole and its metabolites M1 and M4 were: during 0 - 24 hours (8.14 ± 0.80%, 0.560 ± 0.072%, and 1.42 ± 0.19%) and 0 - 60 hours (10.5 ± 1.0%, 0.960 ± 0.084%, and 2.52 ± 0.20%), the average cumulative urinary excretion rates of ornidazole and its metabolites M1 and M4 were: 0 - 24 hours (8.64 ± 0.98%, 0.486 ± 0.074%, and 1.46 ± 0.21%), 0 - 60 hours (11.8 ± 1.0%, 0.888 ± 0.070%, and 2.76 ± 0.20%). The incidence of adverse reactions was similar between the two drugs. CONCLUSION: No chiral inversion of levornidazole occurred in vivo after intravenous administration of levornidazole. The pharmacokinetic parameters and cumulative excretion rates of levornidazole and ornidazole were similar. The safety results were basically consistent between the two drugs.

Population pharmacokinetics of levornidazole in healthy subjects and patients, and sequential dosing regimen proposal using pharmacokinetic/pharmacodynamic analysis.

Although sequential treatment with levornidazole has been used for anaerobic infection in clinical practice, there is no evidence-based dosing regimen. This study aimed to evaluate the pharmacokinetics (PK) of levornidazole in healthy subjects and patients, and to propose an evidence-based sequential dosing regimen by pharmacokinetic/pharmacodynamic (PK/PD) analysis. A population PK model was built using the data of 116 Chinese subjects, including 88 healthy young subjects, 12 healthy elderly subjects, and 16 patients with intra-abdominal anaerobic infection. PK/PD analysis was performed combining the minimum inhibitory concentration (MIC) values of levornidazole against 375 anaerobic strains. Four sequential dosing regimens (500 mg q12h, 1000 mg loading dose followed by 500 mg q12h, 750 mg q24h, and 1000 mg q24h) were evaluated in terms of cumulative fraction of response (CFR) and probability of target attainment (PTA) by Monte Carlo simulation. The concentration data of levornidazole and its active metabolites were described adequately by two- and one-compartment models, respectively. Body weight was identified as a significant covariate of levornidazole clearance. Simulations showed that satisfactory PTA (>90%) was achieved for the four dosing regimens when MIC ≤1 mg/L. Considering the simulation results, patients' safety and compliance, levornidazole 750 mg intravenous infusion q24h for 2 days followed by 750 mg oral dose q24h for 5 days was optimal for Bacteroides spp. with an identified MIC ≤1 mg/L.

The Potential Immunomodulatory Properties of Levornidazole Contribute to Improvement in Experimental Ulcerative Colitis.

The use of an antibiotic with immunomodulatory properties could be fascinating in treating multifactorial inflammatory conditions such as ulcerative colitis (UC). We report our investigations into the immunomodulatory properties of levornidazole, the S-enantiomer of ornidazole, which displayed a tremendous therapeutic potential in UC induced by dextran sodium sulfate (DSS). Levornidazole administration to DSS-colitic mice attenuated the intestinal inflammatory process, with an efficacy better than that shown by 5-amino salicylic acid. This was evidenced by decreased disease activity index, ameliorated macroscopic and microscopic colon damages, and reduced expression of inflammatory cytokines. Additionally, levornidazole displayed anti-inflammatory activity through Caveolin-1-dependent reducing IL-1ß and IL-18 secretion by macrophages contributing to its improvement of the intestinal inflammation, as confirmed in vitro and in vivo. In conclusion, these results pointed out that the immunomodulatory effects of levornidazole played a vital role in ameliorating the intestinal inflammatory process, which would be crucial for the translation of its use into clinical settings.

Design and Evaluation of Sustained Release of Ornidazole by Dental Inserts.

Aim & Background: Ornidazole is an antimicrobial drug used to treat certain types of vaginal, urinary tract, and interstitial infections. The study aims to formulate and evaluate the dental inserts by using a drug candidate to sustained drug release to improve patient compliance, reduce dosing frequency, reduce the risk of dose dumping, and avoid the first-pass metabolism. They have better therapeutic efficacy and fewer side effects. METHODS: The dental inserts were prepared using various polymers alone and in combination with the different ratios of polymers. The evaluation parameters like thickness, drug content, content uniformity, moisture reuptake, weight variation, swelling studies, and erosion studies of the optimized inserts were studied. The in-vivo studies were conducted to determine the reduction of pocket depth in human volunteers. RESULTS: The system containing ethylcellulose and hydroxyl methyl propyl cellulose K100M (4:1) formulation F6 was optimized because drug release was sustained up to 120 hrs concerning other formulations. Optimized formulation followed first-order kinetics and Peppas release kinetics via fickian diffusion. There was no swelling, itching, irritation, and no reduction in the pocket depth in in-vivo studies. CONCLUSION: The study concluded that dental inserts could extend the release of Ornidazole for many hours and also enhance bioavailability. Furthermore, they also help in avoiding the first-pass effect. In vivo studies' observations showed no itching, irritation, swelling, and pocket-depth reduction.

Development and characterization of rapid dissolving ornidazole loaded PVP electrospun fibers.

Gingivitis is a common and mild form of periodontal disease and can be described as a limited inflammation of the gingiva. This study aims to develop and characterize rapid releasing mucoadhesive fibers containing ornidazole with electrospinning process for the treatment of gingivitis. Polyvinylpyrrolidone (PVP) was chosen as a polymer and used at different concentrations of 10%, 12.5%, and 15%. Scanning electron microscopy images showed that fiber diameters increased with increasing polymer concentrations. Tensile strength and elongation at break values of fibers increased with increasing PVP amount, whereas the loading of ornidazole into the fibers decreased these parameters. The contact angle values of all fibers were found to be 0° due to the hydrophilic nature of PVP. Ornidazole was released within 5 min and diffused from all of the fibers faster than that of gel and solution formulations. Electrospun ornidazole fibers were found efficient against Porphyromonas gingivalis in antimicrobial activity studies. The results demonstrated that ornidazole loaded fibers could be a potential drug delivery system for the treatment of gingivitis.

Pharmacokinetics and Pharmacodynamics of Levornidazole in Patients With Intra-abdominal AnaerobicInfection.

PURPOSE: The pharmacokinetic (PK) and pharmacodynamic characteristics of levornidazole were studied in patients with intra-abdominal anaerobic infection to provide the rationale of new clinical dosing regimen of levornidazole. METHODS: A single-center, open, multidose trial was conducted in 16 patients with intra-abdominal anaerobic infection. Patients received levornidazole at 500mg q12h by intravenous infusion for 3 to 7days. The plasma samples collected before and after the last dose were analyzed by the LC-MS/MS method to determine the concentration of levornidazole. The PK parameters of levornidazole were calculated, and the PK profiles of levornidazole after the dosing regimen of 750mg q24h for 7days were simulated based on the linear PK profile of levornidazole. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment (PTA) of both dosing regimens at steady-state against Bacteroides fragilis. FINDINGS: After administration of the last dose of 500mg of levornidazole, the mean (SD) Cmax_ss, AUC0-12, and t1/2 of levornidazole were 24.0 (5.37) µg/mL, 176.59 (29.22) µg·h/mL, and 11.03 (1.34) hours, respectively. The mean (SD) CLss and Vss of levornidazole were 2.90 (0.47) L/h and 45.90 (7.44) L, respectively. The mean (SD) distribution volume of central compartment (V1) and distribution volume of peripheral compartment (V2) were 26.71 (8.51) L and 19.21 (10.86) L, respectively. On the basis of simulation, the accumulation ratio of levornidazole in the 750mg q24h dosing regimen was 30.2% lower than the value in the 500mg q12h dosing regimen. Forthe 2 dosing regimens, the Cmax_ss, AUC0-τ, AUC0-∞, CLss, and Vss did not produce a significant difference between patients and healthy volunteers (P > 0.05). The cumulative fraction of response of levornidazole against B fragilis was >90%, and the probability of target attainment after both dosing regimens was >90%, when the MIC was ≤1 µg/mL. IMPLICATIONS: No significant differences were found in the PK profiles of levornidazole at steady state between the patients with intra-abdominal anaerobic infection and healthy volunteers. The clinical conventional 750mg q24h regimen can achieve similar clinical and microbiological efficacies against anaerobic in the patients after the 500mg q12h regimen.

Design, optimization and characterizations of chitosan fortified calcium alginate microspheres for the controlled delivery of dual drugs.

Periodontal disease is chronic, highly prevalent infectious disease that requires prolonged and controlled delivery of antimicrobial agents into pockets. To achieve this objective, dual antimicrobials encapsulated chitosan fortified calcium alginate (CS-Ca-SA) microspheres were formulated by application of Plackett-Burman factorial design. The microspheres were optimized for particle size (PS), entrapment efficiency (EE) and drug release. The optimized microspheres presented average PS of 74-461 µm and EE of 62.45-86.20% with controlled drug delivery for 120 hours. FTIR disclosed successful complexation between SA and CS. DSC and XRD studies showed changes in the crystallinity of drugs in microspheres. Shape factor and SEM demonstrated spherical to pear-shaped microspheres. Release exponent >0.43 and high diffusion coefficients revealed non-Fickian-based diffusion-limited drug release. CS-Ca-SA microspheres exhibited surface pH of 6.5 ± 0.5, moderate swelling, less erosion and improved mucoadhesion over Ca-SA microspheres. Also, significant antimicrobial activity against Escherichia coli and Staphylococcus aureus and cytocompatibility with L929 cell lines were observed. Further, microspheres exhibited long-term stability on refrigeration. The outcomes of study supported the potential of dual polymer and dual drug-based biodegradable, stable, non-toxic, mucoadhesive, controlled and prolonged drug release microspheres as more patient compliant by administration into periodontal pockets for the management of periodontal disease.

Multi-Stimuli Responsive Self-Assembled Nanostructures Useful for Colon Drug Delivery.

Self-assembled nanoformulations have been finding various applications in biomedical sciences. Here, we have designed and synthesized a small molecule-based amphiphilic conjugate of azobenzene, Azo-PEG-OMe, which self-assembles into nanostructures in an aqueous environment. The formation of nanostructures was evidenced by light scattering and electron microscopic analyses, which revealed the size of the so formed nanostructures ~199 and ~42 nm, respectively. Responsiveness of these nanostructures to various stimuli was demonstrated by enzyme and UV-Vis light exposure, pH and chemical reductant, sodium dithionite. Morphological alterations in the nanostructures on exposure to these stimuli were recorded and subsequently, these nanostructures were demonstrated as efficient carrier of drugs by entrapping an antiprotozoan drug, ornidazole, with ~82% entrapment efficiency. Under influence of different stimuli (light, pH, and enzyme), the drug release behavior displayed good response to each stimulus implying that the projected nanostructures could be used as efficient drug delivery system. Response to azoreductase enzyme further established that the formulation can be used for site specific drug delivery particularly useful for colonic drug delivery.

Clinical Pharmacokinetics of Levornidazole in Elderly Subjects and Dosing Regimen Evaluation Using Pharmacokinetic/Pharmacodynamic Analysis.

PURPOSE: Levornidazole, the levo-isomer of ornidazole, is a third-generation nitroimidazole derivative newly developed after metronidazole, tinidazole, and ornidazole. An open-label, parallel-controlled, single-dose study was conducted for the investigation of the pharmacokinetic (PK) profile of levornidazole and its metabolites in healthy elderly Chinese subjects, and for the evaluation of 2 dosing regimens in the elderly. METHODS: Levornidazole was intravenously administered at 500 mg to healthy elderly (aged 60-80 years) or young subjects (aged 19-45 years). The PK profiles of levornidazole and its metabolites in elderly subjects were evaluated and compared with those in the young group. WinNonlin software was used for simulating the PK profile of levornidazole in the elderly population following the dosing regimens of 500 mg BID and 750 mg once daily for 7 days. Monte Carlo simulation was used for estimating the cumulative fraction of response and probability of target attainment of both dosing regimens against Bacteroides spp. RESULTS: The Cmax, AUC0-24, and AUC0-∞ values of levornidazole in the elderly group were 11.98 µg/mL, 131.36 µg·h/mL, and 173.61 µg·h/mL, respectively. The t1/2, CLt, and mean residence time from time 0 to infinity were 12.21 hours, 2.91 L/h, and 16.46 hours. The metabolic ratios of metabolites (M) 1, 2, 4, and 6 were <3.0%, and that of M16 was 17.70%. The urinary excretion values of levornidazole, M1, M2, M4, M6, and M16 over 96 hours were 10.21%, 0.92%, ~0%, 2.69%, 0.54%, and 41.98%. The PK properties of levornidazole and the urinary excretion of all metabolites were not statistically different between the 2 groups. The cumulative fraction of response was >90% against B fragilis and other Bacteroides spp, and the probability of target attainment was >90% when the minimum inhibitory concentration was ≤1 µg/mL, in both groups. IMPLICATIONS: No dosing regimen adjustment is suggested when levornidazole is used in elderly patients with normal hepatic functioning and mild renal dysfunction. The findings from the PK/PD analysis imply that both regimens may achieve satisfactory clinical and microbiological efficacy against anaerobic infections in elderly patients. Chinese Clinical Trial Registry (http://www.chictr.org.cn) identifier: ChiCTR-OPC-16007938.

In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis.

PURPOSE: This study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model. METHODS: An anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body. The device of 2-compartment PK/PD model was constructed by using digital control of flow rate to simulate 4 regimens of single-dose intravenous infusion of levornidazole to determine the bactericidal activity of levornidazole against the 3 strains of B fragilis within 72 hours. PD parameters such as reduction of colony count within 24 hours (∆Log24h), area under bactericidal curve (AUBC), and 2-hour initial killing rate (IKR) were calculated and correlated with PK/PD parameters. Sigmoid Emax model of levornidazole was established to calculate PK/PD target values to attain corresponding PD effect. FINDINGS: PK and PD validation proved the stability of the model in simulating levornidazole against B fragilis and the precision and accuracy in the results of PK modeling. Cmax and AUC0-24h found only -1.46% and -6.72% differences from the values in vivo. Our study found that ∆Log24h, AUBC, and IKR were more correlated with AUC0-24h/MIC and Cmax/MIC than with %T>MIC. According to ∆Log24h, the PK/PD target values of AUC0-24h/MIC, Cmax/MIC, and %T>MIC of levornidazole against B fragilis were 157.6%, 14.1%, and 56.4%, respectively. IMPLICATIONS: Our findings are useful for optimizing the clinical dosing regimen of levornidazole sodium chloride injection to attain maximal bactericidal effect.

Preparation, in Vitro and in Vivo Evaluations of Compound Calculus Bovis Sativus and Ornidazole Film.

The aim of this study was to develop and to investigate a film of compound Calculus Bovis Sativus (CBS) and ornidazole film. A uniform mucoadhesive film was herein successfully obtained by a film-forming solusion containing insoluable drug. This film, as a valid adjunct for the treatment of oral mucosal ulcer, consisted of two main drugs (CBS, ornidazole) and three polymers (hydroxypropyl methyl cellulose, chitosan, poly(vinyl alcohol) (PVA)). The film was prepared with the film-forming suspension, using casting-solvent evaporation technique. The drug content, release behavior, swelling index and mucoadhesive properties of the film were detected. Then the effects of the prepared film on a glacial acetic acid-induced oral mucosal ulceration model of rabbits were evaluated. Moreover, the in vivo release of bilirubin and ornidazole in saliva were also detected in the oral mucosae of healthy volunteers. The films showed favorable in vitro drug release behaviors and swelling properties. Mucosal wounds in the animals were significantly relieved. With the films well tolerated, the salivary concentrations of ornidazole were maintained above the minimum inhibitory concentration against CBS for about 2 h. The compound CBS and ornidazole film functioned better than the film only containing CBS and ornidazole did. Therefore, it is a potentially efficient drug delivery system for the treatment of oral ulcers.

Improved pharmacokinetic profile of levornidazole following intravenous infusion of 750mg every 24h compared with 500mg every 12h in healthy Chinese volunteers.

Levornidazole is the levo-isomer of ornidazole with similar anti-anaerobic activity and lower central neurotoxicity compared with ornidazole. This open-label, parallel, randomised, multidose trial was conducted to compare the pharmacokinetics and safety of levornidazole following intravenous (i.v.) infusion 750mg every 24h (q24h) (test group, 12 subjects) versus 500mg every 12h (q12h) (reference group, 12 subjects) for 7 days in healthy Chinese volunteers. Following i.v. infusion for 7 days, the test group showed a 33.8% lower accumulation ratio (AR) and a 45.0% higher volume of distribution of levornidazole than the reference group. The cumulative urinary excretion rate of levornidazole during the 0-72h period (Ae0-72) was 16.6±20.9% in the test group and 24.2±5.7% in the reference group. The metabolite M1/parent and M4/parent ratios were, respectively, 2.18±0.77% and 2.94±0.37% in test group and 3.15±1.09% and 3.18±0.34% in the reference group. The Ae0-72 of M1, M2 and M4 were all <10% in both groups. Both regimens were well tolerated. Drug-related adverse events were generally transient and were mild or moderate in severity. These findings support the recommendation of i.v. infusion of levornidazole 750mg q24h in clinical practice, which shows a lower AR and similar safety compared with the conventional 500mg q12h regimen. [Chinese Clinical Trial Registry identifier: ChiCTR-IPR-14005574.].

Effects of the ornidazole enantiomers on the central nervous system: Involvement of the GABAA receptor.

This is the preliminary study of the sedative and muscle relaxation activity of ornidazole enantiomers, which are widely used in the treatment of susceptible protozoal infections and anaerobic bacterial infections. Adverse effects on the central nervous system (CNS) are the main side effects of ornidazole during its clinical application. The aim of this study was to compare the different central inhibitory effects between S-(-) ornidazole and R-(+) ornidazole in mice and clarify the possible mechanisms. In the present study, central effects of ornidazole were evaluated by open-field test and rota-rod test, and such effects were reversed by pre-treatment with flumazenil (i.p., 10 mg/kg) suggesting that ornidazole exhibits such action by interacting with the GABAergic system. Then, the functional difference between S-(-) ornidazole and R-(+) ornidazole was further explored by evaluating the contents of glutamate (Glu) and γ-aminobutyric acid (GABA) in the brain, and Western blot was used to measure glutamic acid decarboxylase (GAD65/67) expression in the mice cerebral cortex. We found that R-(+) ornidazole mediated an increase in GABA level while decreased the level of glutamate through upregulation of GAD65/67 in the cerebral cortex. Taken together, our study suggests that R-(+) ornidazole mediate stronger central inhibitory effects than S-(-) ornidazole through interaction with the GABAergic system.

Stimulus-Responsive, Biodegradable, Biocompatible, Covalently Cross-Linked Hydrogel Based on Dextrin and Poly(N-isopropylacrylamide) for in Vitro/in Vivo Controlled Drug Release.

A novel stimulus-sensitive covalently cross-linked hydrogel derived from dextrin, N-isopropylacrylamide, and N,N'-methylene bis(acrylamide) (c-Dxt/pNIPAm), has been synthesized via Michael type addition reaction for controlled drug release application. The chemical structure of c-Dxt/pNIPAm has been confirmed through Fourier transform infrared (FTIR) spectroscopy and (1)H and (13)C NMR spectral analyses. The surface morphology of the hydrogel has been studied by field emission scanning electron microscopic (FE-SEM) and environmental scanning electron microscopic (E-SEM) analyses. The stimulus responsiveness of the hydrogel was studied through equilibrium swelling in various pH media at 25 and 37 °C. Rheological study was performed to measure the gel strength and gelation time. Noncytotoxicity of c-Dxt/pNIPAm hydrogel has been studied using human mesenchymal stem cells (hMSCs). The biodegradability of c-Dxt/pNIPAm was confirmed using hen egg lysozyme. The in vitro and in vivo release studies of ornidazole and ciprofloxacin imply that c-Dxt/pNIPAm delivers both drugs in a controlled way and would be an excellent alternative for a dual drug carrier. The FTIR, powder X-ray diffraction (XRD), and UV-vis-near infrared (NIR) spectra along with the computational study predict that the drugs remain in the matrix through physical interaction. A stability study signifies that the drugs (ornidazole ∼97% and ciprofloxacin ∼98%) are stable in the tablet formulations for up to 3 months.

In vitro simulation of in vivo pharmacokinetic model with intravenous administration via flow rate modulation.

The aim of this paper was to propose a method of flow rate modulation for simulation of in vivo pharmacokinetic (PK) model with intravenous injection based on a basic in vitro PK model. According to the rule of same relative change rate of concentration per unit time in vivo and in vitro, the equations for flow rate modulation were derived using equation method. Four examples from literature were given to show the application of flow rate modulation in the simulation of PK model of antimicrobial agents in vitro. Then an experiment was performed to confirm the feasibility of flow rate modulation method using levo-ornidazole as an example. The accuracy and precision of PK simulations were evaluated using average relative deviation (ARD), mean error and root mean squared error. In vitro model with constant flow rate could mimic one-compartment model, while the in vitro model with decreasing flow rate could simulate the linear mammillary model with multiple compartments. Zero-order model could be simulated using the in vitro model with elevating flow rate. In vitro PK model with gradually decreasing flow rate reproduced the two-compartment kinetics of levo-ornidazole quite well. The ARD was 0.925 % between in vitro PK parameters and in vivo values. Results suggest that various types of PK model could be simulated using flow rate modulation method without modifying the structure. The method provides uniform settings for the simulation of linear mammillary model and zero-order model based on in vitro one-compartment model, and brings convenience to the pharmacodynamic study.

Simultaneous determination of ornidazole and its main metabolites in human plasma by LC-MS/MS: application to a pharmacokinetic study.

BACKGROUND: Ornidazole is a 5-nitroimidazole antimicrobial agent used for almost 40 years. A novel LC-MS/MS assay was developed and validated for the simultaneous determination of ornidazole and its main metabolites (M3, M6, M16-1, and M16-2) in human plasma. RESULTS: After extraction from 100 µl of plasma by protein precipitation with acetonitrile, all the analytes were separated on a Capcell PAK MG C18 column (100 × 4.6 mm, 5 µm) within 5.0 min and detected by ESI-MS/MS in the positive mode. The validation results met the acceptance criteria as per the US FDA and EMA guidelines. CONCLUSION: The validated method was successfully applied to a pharmacokinetic study after oral administration of 1000 mg ornidazole to six healthy Chinese volunteers.

Investigation of chiral inversion and pharmacokinetics of laevo-ornidazole by high-performance liquid chromatography.

WHAT IS KNOWN AND OBJECTIVE: Laevo-ornidazole is an enantiomer of ornidazole, a 5-nitroimidazole antimicrobial agent. It is not known whether chiral inversion of laevo-ornidazole occurs in humans. The objective of this study was to investigate the possible chiral inversion and pharmacokinetics of the drug in vivo. METHODS: We developed a stereo-specific high-performance liquid chromatographic method for investigating chiral inversion of the drug and a standard high-performance liquid chromatography (HPLC) for the routine assay of the drug in pharmacokinetic studies. We report on the pharmacokinetics of the drug following single dose and multiple doses and investigate the effect of food in healthy volunteers. RESULTS AND DISCUSSION: There was no chiral inversion of laevo-ornidazole in vivo. In the pharmacokinetic study of the drug in healthy Chinese volunteers, food intake affected the absorption rate of laevo-ornidazole but not the extent. WHAT IS NEW AND CONCLUSION: We present the first reported method for the chiral separation of ornidazole in human plasma. We demonstrate the absence of chiral inversion of laevo-ornidazole in vivo. Given the absence on in vivo chiral inversion, we also report and validate a simplified non-chiral method for the determination of laevo-ornidazole. We show that although food can affect the absorption rate of laevo-ornidazole, the extent was unaffected.

[Correlation of ornidazole concentration in saliva and serum of healthy volunteers].

OBJECTIVE: To investigate the distribution of ornidazole in the salivary and serum of healthy adults and explore the feasibility of monitoring serum drug concentration with salivary. METHODS: Six volunteers received a single dose of 0.6 g ornidazole via intravenous infusion. The concentrations of ornidazole in the saliva and serum were assayed by high-performance liquid chomatography, and the correlation of the drug concentrations in saliva to that in serum was analyzed. RESULTS: The concentration of ornidazole in the saliva was strongly associated with that in the serum (r = 0.825-0.969), and the ratio of saliva-to-serum concentration (S/P) of ornidazole was 0.99 ± 0.13. CONCLUSION: Detection of saliva ornidazole concentration is feasible for monitoring the therapeutic concentration of ornidazole.

Novel pepper extract for enhanced P-glycoprotein inhibition.

OBJECTIVES: Piperine is one of the most promising bioenhancers to date. Methods used for its extraction suffer from drawbacks such as use of organic solvents, poor extraction efficiency, tedious and expensive methodology. These methods are not encouraged with a view to reducing global warming. The objective was therefore to develop an alternative solvent-free extraction method. METHODS: An aqueous extract of long pepper fruits was prepared using hydrophilic lipid Gelucire 44/14 as the extracting aid and this was compared with an alcoholic extract. Extracts were characterized using high-performance thin layer chromatography and differential scanning calorimetry. P-glycoprotein (P-gp) inhibitory activity of the aqueous and alcoholic extracts and pure piperine was compared using an in-vitro everted rat intestinal model using ornidazole as the model drug. The study was performed using two oral pretreatment dose levels (10 and 20 mg/kg) and durations (1 and 3 days). Exsorption of ornidazole from serosal to mucosal surface was monitored. KEY FINDINGS: P-gp inhibitory activity of the aqueous extract was comparable with that of pure piperine (P > 0.05) and was significantly higher than the alcoholic extract (P < 0.05). Pure piperine and the aqueous extract exhibited significant P-gp inhibitory activity compared with control, which was irrespective of oral pretreatment dose and duration levels. No significant effect of oral pretreatment duration of the aqueous extract was observed. The observed enhancement in P-gp inhibitory activity of the aqueous extract may have been attributed to the P-gp inhibitory potential of Gelucire 44/14 and its efficient extraction and solubility enhancement ability. CONCLUSIONS: In the field of phytopharmaceuticals efficient and eco-friendly extraction processes are still a goal to be achieved. Extraction with Gelucire 44/14 could be a potential method of extraction for phytopharmaceuticals. Compared with conventional methods of extraction it is more efficient, easier to prepare, eco-friendly and scalable.

Effect of rifampicin pretreatment on the transport across rat intestine and oral pharmacokinetics of ornidazole in healthy human volunteers.

Increased exsorption of ornidazole was observed from different parts of the small intestine of the rat after pretreated with rifampicin and sodium butyrate by the everted sac method. Based on the in vitro studies the effect of rifampicin pretreatment on the pharmacokinetics of ornidazole was investigated in eight healthy male volunteers. After an overnight fast, 500 mg ornidazole was administered to the volunteers, either alone or after 6 days pretreatment with a once daily dose of 600 mg rifampicin. Serum concentrations of ornidazole were estimated by reverse phase HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program Win Nonlin 1.1. Rifampicin preteatment resulted in a significant decrease in AUC, C(max) and t1/2, by 21.16%, 20.43% and 18.11%, respectively. Clearance was increased significantly by 32.14%. This may be due to increased induction of cytochrome P450 enzymes and/or increased expression of P-glycoprotein. This interaction may have clinical significance when ornidazole is co-administered with rifampicin in chronic treatment conditions, such as tuberculosis, leprosy and other infections of joints, bones, etc.