Development and validation of ultra-performance liquid chromatography-tandem mass spectrometric methods for simultaneous and rapid determination of contezolid and its major metabolite M2 in plasma and urine samples and its application to a study in subjects with moderate liver impairment.

Contezolid is a novel oxazolidinone antibiotic with good antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. For the purpose to further characterize the pharmacokinetics of contezolid and its major metabolite M2, accurate and rapid ultra-performance liquid chromatography-tandem mass spectrometric assays (UPLC-MS/MS) were developed and validated for simultaneous quantification of contezolid and M2 in human plasma and urine. The plasma samples were pretreated by liquid-liquid extraction. The automated solid phase extraction method was used to preprocess urine samples. ACQUITY UPLC® BEH C8 (2.1 mm × 100 mm, 1.7 µm) column was used to separate the analytes with a gradient mobile phase of acetonitrile and water at a flow rate of 0.4 mL/min. The calibration curves showed good linearity over the concentration ranges of 0.0100-5.00 µg/mL for contezolid in plasma and urine, 0.00200-1.00 µg/mL in plasma and 0.0200-10.0 µg/mL in urine for M2, respectively. For both plasma and urine assays, the intra- and inter-batch accuracy and precision were within 15% for all quality control levels, including the lower limit of quantitation. The methods were fully validated and successfully applied to a pharmacokinetic study of contezolid tablets in subjects with moderate hepatic impairment.

Simultaneous determination of a novel oxazolidinone anti-tuberculosis OTB-658 and its metabolites in monkey blood by LC-MS/MS.

OTB-658, a novel oxazolidinone anti-tuberculosis agent, has potent antibacterial activity against Mycobacterium tuberculosis, especially multi-drug resistant tuberculosis (MDR-TB) in vitro and in vivo. In this study, after metabolite identification of parent drug OTB-658, a specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated to quantify OTB-658 and its metabolites OTB-665 and OTB-698 in monkey blood. HHY-1442, an analogue compound of OTB-658, was used as the internal standard. Blood samples were prepared by direct protein precipitation. Separation was performed on a Zorbax SB C18 column (50 mm × 2.1 mm, 3.5 µm) with a gradient mobile phase of methanol/water at a flow rate of 0.3 mL/min. The detection was conducted by a positive electrospray ionization in multiple-reaction monitoring mode on a triple quadrupole MS. The monitored transitions were m/z 382.2 â†’ 221.1 for OTB-658, m/z 398.2 â†’ 308.1 for OTB-665, m/z 414.1 â†’ 372.3 for OTB-698 and m/z 418.2 â†’ 311.3 for HHY-1442, respectively. Good linearity was observed over the range of 10-2000 ng/mL for OTB-658 and OTB-665, and 5-1000 ng/mL for OTB-698. All the intra-day and inter-day precision for the three analytes was below 8.4%, and the accuracy ranged from 96.0% to 106.0%. All analytes were stable during storage, preparation, and analytical procedures. The validated method was successfully applied to pharmacokinetic and bioavailability studies of OTB-658 in cynomolgus monkeys and the absolute bioavailability of OTB-658 was 25.0% at an oral dose of 10 mg/kg.

Comparative pharmacokinetics of tedizolid in rat plasma and cerebrospinal fluid.

To investigate the possibility of tedizolid phosphate's application in the treatment of intracranial infection, a preclinical comparative pharmacokinetic study was designed. Based on the assumption that the classic efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) may participate in the transportation of TDZ, two groups of rats were intravenously administered 6 mg/kg tedizolid phosphate alone or 6 mg/kg tedizolid phosphate combined with 1 mg/kg elacridar which was an inhibitor of P-gp and BCRP. Plasma and cerebrospinal fluid samples were collected according to a pharmacokinetic schedule. All the plasma and cerebrospinal fluid samples were assessed with a validated LC-MS/MS method. The penetration ratio of tedizolid from the blood to cerebrospinal fluid was calculated, and a comparison of the penetration ratios between the two groups was made. The mean Cmax of tedizolid in the CSF in the tedizolid phosphate group and the tedizolid phosphate combined with elacridar group was 154 ng/mL and 300 ng/mL, respectively, and the mean penetration ratio of tedizolid in the tedizolid phosphate group and the tedizolid phosphate combined with elacridar group was 2.16% and 3.53%, respectively. The relatively high Cmax in the CSF proved the possibility of tedizolid phosphate's application in the treatment of intracranial infection, and the higher penetration ratios, Cmax, csf and AUCcsf of the rats in co-administered elacridar group than those in the single-administration group indicated that the transporters P-gp and BCRP might be involved in the transportation of tedizolid.

Concentrations of thiocyanate and goitrin in human plasma, their precursor concentrations in brassica vegetables, and associated potential risk for hypothyroidism.

Brassica vegetables are common components of the diet and have beneficial as well as potentially adverse health effects. Following enzymatic breakdown, some glucosinolates in brassica vegetables produce sulforaphane, phenethyl, and indolylic isothiocyanates that possess anticarcinogenic activity. In contrast, progoitrin and indolylic glucosinolates degrade to goitrin and thiocyanate, respectively, and may decrease thyroid hormone production. Radioiodine uptake to the thyroid is inhibited by 194 µmol of goitrin, but not by 77 µmol of goitrin. Collards, Brussels sprouts, and some Russian kale (Brassica napus) contain sufficient goitrin to potentially decrease iodine uptake by the thyroid. However, turnip tops, commercial broccoli, broccoli rabe, and kale belonging to Brassica oleracae contain less than 10 µmol of goitrin per 100-g serving and can be considered of minimal risk. Using sulforaphane plasma levels following glucoraphanin ingestion as a surrogate for thiocyanate plasma concentrations after indole glucosinolate ingestion, the maximum thiocyanate contribution from indole glucosinolate degradation is estimated to be 10 µM, which is significantly lower than background plasma thiocyanate concentrations (40-69 µM). Thiocyanate generated from consumption of indole glucosinolate can be assumed to have minimal adverse risks for thyroid health.

Pharmacokinetics and elimination efficiency of linezolid during dialysis.

Linezolid (LZD) is an option for treating infections caused by multi-resistant Gram-positive bacteria. The protein-binding rate of LZD markedly influences its elimination by dialysis, with limited data suggesting that LZD is cleared by intermittent hemodialysis. Here, we investigated the protein-binding rate and elimination efficiency of LZD in a sepsis patient receiving dialysis. The oral administration of LZD at 600 mg/day resulted in protein-binding and free rates of the drug of 20.4% and 79.6%, respectively, 24 h after administration. By comparing the LZD concentration before and after dialysis, the elimination efficiency of free LZD as a result of dialysis was found to be 40.6%. Our sepsis patient showed higher plasma concentrations of LZD at trough after hemodialysis than the reported concentrations in normal renal function patients. However, it is not clear from our present findings if a relationship exists between myelosuppression and plasma LZD concentration.

Quantitative determination of zolmitriptan in rat blood and cerebrospinal fluid by reversed phase HPLC-ESI-MS/MS analysis: application to in vivo preclinical pharmacokinetic study.

A fast HPLC-ESI-MS/MS method has been developed and validated for the quantification of the potent and selective antimigraine zolmitriptan in rat blood and cerebrospinal fluid (CSF). The assay has been then applied for in vivo preclinical studies. The analytical determination has been used to obtain pharmacokinetics of zolmitriptan in the two biological matrices after its intravenous or nasal administration. Liquid-liquid extraction of zolmitriptan was performed from 100 µL rat blood samples in the presence of N(6)-cyclopentyladenosine (internal standard) with the employment of ethyl acetate. Calibration standards were prepared by using blood matrix and following the same liquid-liquid extraction procedure. CSF samples were analyzed without any pre-treatment steps and by using an external calibration method in pure water matrix. Chromatographic separation was performed under reversed phase and a gradient elution condition on a C18 packed column (100 × 2.0 mm, 2.5 µm particles diameter). The mobile phase was a mixture between acetonitrile, water and formic acid (0.1% v/v). The applied HPLC-MS/MS method allowed low limits of detection, as calculated from calibration curves, of 6.6 and 24.4 ng/mL for water matrix and rat blood extracts, respectively. Linearity of the calibration curves was established up to 5 µM (1.44 µg/mL), as well as good assay accuracy. The intravenous infusion of 20 µg zolmitriptan to male Sprague-Dawley rats produced blood concentrations ranging from 9.4±0.7 to 1.24±0.07 µg/mL within 10 h, with a terminal half-life of 3.4±0.2h. The nasal administration of a water suspension of 20 µg zolmitriptan produced blood concentrations ranging from 2.92±0.21 to 0.85±0.07 µg/mL within 6h. One hour after zolmitriptan intravenous infusion or nasal administration, its CSF concentrations were 0.0539±0.0016 and 0.0453±0.0012 µg/mL, respectively. This study determined the suitability of the herein proposed method to investigate the pharmacokinetics of zolmitriptan after its administration by means of novel formulations and, hence, to evaluate the efficacy of innovative nose-to-brain drug delivery in preclinical studies.

Development of novel molecularly imprinted solid-phase microextraction fibers and their application for the determination of antibiotic drugs in biological samples by SPME-LC/MS(n).

Novel molecularly imprinted polymer (MIP)-coated fibers for solid-phase microextraction (SPME) fibers were prepared by using linezolid as the template molecule. The characteristics and application of these fibers were investigated. The polypyrrole, polythiophene, and poly(3-methylthiophene) coatings were prepared in the electrochemical polymerization way. The molecularly imprinted SPME coatings display a high selectivity toward linezolid. Molecularly imprinted coatings showed a stable and reproducible response without any influence of interferents commonly existing in biological samples. High-performance liquid chromatography with spectroscopic UV and mass spectrometry (MS) detectors were used for the determination of selected antibiotic drugs (linezolid, daptomycin, amoxicillin). The isolation and preconcentration of selected antibiotic drugs from new types of biological samples (acellular and protein-free simulated body fluid) and human plasma samples were performed. The SPME MIP-coated fibers are suitable for the selective extraction of antibiotic drugs in biological samples.

Pulmonary disposition of tedizolid following administration of once-daily oral 200-milligram tedizolid phosphate in healthy adult volunteers.

This study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC(0-24)) for ELF and AM relative to the free AUC(0-24) (fAUC(0-24)) in plasma. The half-life and volume of distribution in plasma were 9.23 ± 2.04 h and 108.25 ± 20.53 liters (means ± standard deviations), respectively. Total AUC(0-24) in plasma was 25.13 ± 5.78 µg · h/ml. Protein binding was 89.44% ± 1.58%, resulting in a mean fAUC(0-24) of 2.65 ± 0.72 µg · h/ml in plasma. Mean concentrations (µg/ml) at 2, 6, 12, and 24 h were 9.05 ± 3.83, 4.45 ± 2.18, 5.62 ± 1.99, and 1.33 ± 0.59 in ELF and 3.67 ± 1.02, 4.38 ± 2.18, 1.42 ± 0.63, and 1.04 ± 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.

Usefulness of monitoring linezolid trough serum concentration in prolonged treatments.

Linezolid has proven valuable in musculoskeletal infections, however, failure and resistance have been described and toxicity is worrisome when more than 28 days are necessary. We describe the first 5 cases in whom linezolid trough serum concentrations were weekly measured and its relationship with clinical outcome and toxicity.

Influence of linezolid clearance on the induction of thrombocytopenia and reduction of hemoglobin.

INTRODUCTION: Although linezolid (LZD) has proven effective for the treatment of infections caused by multidrug-resistant Gram-positive cocci, thrombocytopenia and anemia associated with reduced hemoglobin (Hb) levels are common side effects. To study the association between the development of these adverse effects and blood LZD levels, the authors evaluated the correlation between LZD clearance (LZD-CL), platelet (PLT) counts and Hb levels. METHODS: Sixteen patients with methicillin-resistant Staphylococcus aureus infection were administered LZD over a period of 4 to 41 days, and blood was collected at variable time points beginning on day 4 (n = 31). Blood LZD levels were measured by high-performance liquid chromatography, and LZD-CL was estimated by the population pharmacokinetics mean parameter and Bayesian methods. The relationship between the estimated LZD-CL and reductions in PLT counts and Hb levels was then evaluated by regression analysis. RESULTS: During the LZD treatment period, a weak correlation was identified between the LZD-CL rate and PLT counts (r(2) = 0.31, n = 31). Significantly, the regression analysis between LZD-CL and Hb levels showed a stronger correlation (r(2) = 0.54, n = 31), with Hb levels clearly decreasing with reductions in the LZD-CL rate. CONCLUSIONS: In patients undergoing treatment with LZD, low LZD-CL rates correlated with reductions of both PLT counts and Hb levels, suggesting that increase of blood LZD levels influences hematopoietic function. Because a strong correlation was noted between LZD-CL and Hb levels, closely monitoring changes in Hb levels during treatment with LZD may detect the development of adverse effects such as thrombocytopenia and anemia.

New coated SPME fibers for extraction and fast HPLC determination of selected drugs in human blood.

Polythiophene (PTh) and polypyrrole (PPy) as sorbent phases for solid phase microextraction (SPME) were applied in order to extract the multi-resistant Staphylococcus aureus (MRSA) antibiotic drugs (linezolid and daptomycin) from whole blood followed by high performance liquid chromatography (HPLC) determination with UV detection. Relative standard deviations (RSDs) of in vitro and pseudo in vivo measurements performed in whole blood were in the range of 4.58-15.91% and 6.09-17.33% for linezolid and daptomycin, respectively. Determination coefficients (R(2)) were in range of 0.9884-0.9945 and 0.9807-0.9818 for linezolid and daptomycin, respectively. This study proved better adsorption capacity of PTh SPME coating compared to PPy coating for both, linezolid and daptomycin.

Polypyrrole solid phase microextraction: A new approach to rapid sample preparation for the monitoring of antibiotic drugs.

Simple or even rapid bioanalytical methods are rare, since they generally involve complicated, time-consuming sample preparation from the biological matrices like LLE or SPE. SPME provides a promising approach to overcome these limitations. The full potential of this innovative technique for medical diagnostics, pharmacotherapy or biochemistry has not been tapped yet. In-house manufactured SPME probes with polypyrrole (PPy) coating were evaluated using three antibiotics of high clinical relevance - linezolid, daptomycin, and moxifloxacin - from PBS, plasma, and whole blood. The PPy coating was characterised by scanning electron microscopy. Influences of pH, inorganic salt, and blood anticoagulants were studied for optimum performance. Extraction yields were determined from stagnant media as well as re-circulating human blood using the heart-and-lung machine model system. The PPy-SPME fibres showed high extraction yields, particularly regarding linezolid. The reproducibility of the method was optimised to achieve RSDs of 9% or 17% and 7% for SPME from stagnant or re-circulating blood using fresh and re-used fibres, respectively. The PPy-SPME approach was demonstrated to meet the requirements of therapeutic monitoring of the drugs tested, even from re-circulating blood at physiological flow rates. SPME represents a rapid and simple dual-step procedure with potency to significantly reduce the effort and expenditure of complicated sample preparations in biomedical analysis.

Determination of antibiotic drug concentrations in circulating human blood by means of solid phase micro-extraction.

BACKGROUND: Promising results in animals have shown the diagnostic potential of polypyrrole coated SPME fibres introduced directly into the blood stream. This study was intended to extend this technique to a clinically relevant antibiotic drug under close to physiological conditions in human blood. METHODS: An artificial vein system was built up from heart and lung machine components. Determination of Linezolid (0-15 mug/mL) was performed by SPME from the flowing system ("online", flow velocities 2-50 cm/s), from blood withdrawn from the system ("offline") and by means of a SPE/HPLC method. SPME was done using new fibres ("new") for each analysis, and in the way that one fibre was reused ("re") for one series of measurements. RESULTS: Drug SPME did not depend on blood flow velocities. Linear regression of data (concentration vs. amount extracted) yielded R(2)=0.998 for SPE/HPLC, R(2)=0.955 for SPME(online_new), 0.929 for SPME(online_re), 0.929 SPME(offline_new), 0.973 for SPME(offline_re), RSD were 52% (SPME(online_new)), 10% (SPME(online_re)), 47% (SPME(offline_new)), 18% (SPME(offline_re)), 8% (SPE/HPLC). CONCLUSIONS: In-vein SPME has the potential to minimize blood requirement for diagnostic purposes and to speed up analysis of clinically relevant drugs, if inter-fibre variation can be reduced through standardized manufacturing.

Linezolid tissue penetration and serum activity against strains of methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility in diabetic patients with foot infections.

OBJECTIVES: Linezolid soft tissue penetration and serum antimicrobial activity were analysed in six patients with peripheral vascular disease and severe diabetic foot infections requiring surgical intervention. METHODS: Blood draws (1, 3, 6, 9 and 12 h after initiation of a 1 h infusion) and a viable soft tissue sample at the site of infection were obtained in patients receiving linezolid (600 mg every 12 h) on the day of surgery. Concentrations of linezolid were determined by HPLC in both tissue (pre-treated with tissue lysis buffer) and serum. In addition, serum inhibitory and bactericidal activity (dilution titres 1:2-1:32) of linezolid was determined in these patients against strains of methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin (vancomycin MICs = 2, 4, 8, 256 and >256 mg/L). RESULTS: Linezolid concentrations in tissue were found to be 51% (range, 18% to 78%) of simultaneous serum concentrations. Rapid (1 h) and prolonged (12 h) inhibitory activity (titres > or = 1:2) was observed for linezolid against each of the study isolates. Furthermore, bactericidal activity (titres > or = 1:2) was observed for at least 6 h (50% of the dosing interval) against four of these five strains. CONCLUSIONS: These findings suggest that linezolid could be effective in the treatment of multidrug-resistant MRSA even when concentrations at the infection site are diminished due to impaired blood flow.

The pharmacokinetics of linezolid in the non-inflamed human eye.

AIM: This study describes the ocular pharmacokinetics of linezolid, an antibiotic with broad spectrum activity against those Gram positive bacteria that are the most frequent cause of postoperative endophthalmitis. METHOD: Patients undergoing routine cataract surgery were given a single oral 600 mg dose of linezolid at a variable time before surgery. Aqueous and serum levels of linezolid were assayed by high performance liquid chromatography, and a pharmacokinetic curve constructed from the pooled results. RESULTS: Orally administered linezolid rapidly achieves levels in the aqueous of non-inflamed eyes that exceed the concentration required to kill Gram positive bacteria (maximum mean concentration 6.8 (SD 1.2) microg/ml at 2-4 hours post-dose). An effective concentration is maintained for at least 12 hours, the standard interdose interval for this antimicrobial. CONCLUSION: Linezolid offers the possibility of a rapid, oral approach to effective treatment of most cases of postoperative endophthalmitis, with the potential of improving visual outcome.

Serum and sputum concentrations following the oral administration of linezolid in adult patients with cystic fibrosis.

OBJECTIVES: Linezolid is a new oxazolidinone antibiotic with efficacy against a broad range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). In this study, we have determined the serum and sputum linezolid concentrations in adults with cystic fibrosis (CF) following oral drug administration. METHODS: Eleven adult patients with CF were recruited. Subjects received 600 mg of linezolid orally every 12 h for a total of six doses. Serum and sputum levels were measured just before and at 2 h after the final dose of linezolid. A further serum level was measured at 4 h. RESULTS: Ten adult patients completed the study. Mean (s.d.) serum linezolid concentrations were 2.3 mg/L (1.5) at 12 h following the fifth dose. At 2 and 4 h following the sixth dose, concentrations were 13.5 (4.3) and 8.1 (3.3). Mean (s.d.) linezolid sputum concentrations were 3.6 (2.1) and 17.4 (7.2) mg/L at 0 and 2 h following drug administration. CONCLUSIONS: The oral administration of linezolid results in good sputum penetration in patients with CF. Mean levels exceed the required MIC for the treatment of MRSA for >80% of the dosing period for serum and the majority of the dosing period for sputum.

The pharmacokinetics of linezolid are not affected by concomitant intake of the antioxidant vitamins C and E.

In vitro metabolism experiments have suggested a possible role for endogenous reactive oxygen species (ROS) in the in vivo clearance of linezolid, a synthetic antibiotic of the oxazolidinone class. This observation has resulted in the hypothesis that dietary antioxidant supplements might disturb the balance of ROS in vivo and thereby lower the clearance of linezolid. The purpose of this open-label, two-group parallel design study was to investigate whether continuous intake of widely used vitamin C or vitamin E will affect the pharmacokinetics of linezolid. A total of 28 healthy volunteers (27 male and 1 female), including 22 of Chinese origin, were administered a single oral dose of 600 mg linezolid on days 1 and 8. Half of the subjects received daily oral doses of 1000 mg vitamin C on days 2 through 9, whereas the other half were administered daily oral doses of 800 IU vitamin E during the same time period. Serial blood samples for assessment of the pharmacokinetic parameters of linezolid and its two inactive metabolites were collected on days 1 and 8, whereas vitamin concentrations were measured prior to and after the vitamin intake on these days. Urine was collected on days 1 and 8 to assess the fraction of dose excreted as linezolid and its major metabolites. All linezolid samples were analyzed according to validated HPLC/MS/MS methods. Linezolid was well tolerated in both groups with no reported clinically significant adverse events. No significant changes were found between the day 1 and day 8 AUC0- infinity and Cmax values of linezolid in either the vitamin C treatment group (p = 0.55 and p = 0.64, respectively) or the vitamin E treatment group (p = 0.06 and p = 0.49, respectively). Assessment of other pharmacokinetic parameters did not imply any change across the study groups. In conclusion, linezolid pharmacokinetics are not affected by concomitant administration with vitamins C and E. Therefore, no dose adjustment is necessary in patients taking vitamin C or vitamin E. These no-effect drug interaction data are in accord with current literature indicating that antioxidant vitamins have only subtle effects on overall ROS balance in vivo.

Pharmacology of novel heteroaromatic polycycle antibacterials.

Heteroaromatic polycycle (HARP) compounds are a novel class of small (M(w), 600 to 650) DNA-binding antibacterials. HARP compounds exhibit a novel mechanism of action by preferentially binding to AT-rich sites commonly found in bacterial promoters and replication origins. Noncovalent binding in the minor groove of DNA results in inhibition of DNA replication and DNA-dependent RNA transcription and subsequent bacterial growth. HARP compounds have previously been shown to have potent in vitro activities against a broad spectrum of gram-positive organisms. The present report describes the extensive profiling of the in vitro and in vivo pharmacology of HARP antibacterials. The efficacies of representative compounds (GSQ-2287, GSQ-10547, and GSQ-11203), which exhibited good MIC activity, were tested in murine lethal peritonitis and neutropenic thigh infection models following intravenous (i.v.) administration. All compounds were efficacious in vivo, with potencies generally correlating with MICs. GSQ-10547 was the most potent compound in vitro and in vivo, with a 50% effective dose in the murine lethal peritonitis model of 7 mg/kg of body weight against methicillin-sensitive Staphylococcus aureus (MSSA) and 13 mg/kg against methicillin-resistant S. aureus (MRSA). In the neutropenic mouse thigh infection model, GSQ-11203 reduced the bacterial load (MRSA and MSSA) 2 log units following administration of a 25-mg/kg i.v. dose. In a murine lung infection model, treatment with GSQ-10547 at a dose of 50 mg/kg resulted in 100% survival. In addition to determination of efficacy in animals, the pharmacokinetic and tissue disposition profiles in animals following administration of an i.v. dose were determined. The compounds were advanced into broad safety screening studies, including screening for safety pharmacology, genotoxicity, and rodent toxicity. The results support further development of this novel class of antibiotics.

The pharmacokinetics of the antimigraine compound zolmitriptan in Japanese and Caucasian subjects.

BACKGROUND: Zolmitriptan is a 5HT(1B/1D) receptor agonist effective in the acute treatment of migraine. Clinical trials in the USA and Europe have demonstrated the optimal oral therapeutic dose to be 2.5 mg. The 2.5-mg oral tablet has recently been licensed in Japan. OBJECTIVE: To compare the pharmacokinetics of zolmitriptan and its metabolites in Japanese and Caucasian subjects and evaluate the effect of gender on these pharmacokinetics in Japanese volunteers. METHODS: In this open, parallel-group study, 30 Japanese and 30 Caucasian volunteers (20-45 years) received a single 2.5-mg zolmitriptan tablet in the fasting state. Blood samples were taken up to 15 h post-dose to determine plasma concentrations of zolmitriptan and its active metabolite, 183C91. Urinary excretion of zolmitriptan, 183C91 and the inactive N-oxide and indole acetic acid metabolites were measured over 24 h. RESULTS: Japanese volunteers were, on average, smaller and lighter than Caucasian volunteers. Plasma-concentration profiles of zolmitriptan and 183C91 were similar in the two groups. Although geometric mean zolmitriptan and 183C91 area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C(max)) were slightly higher in Japanese subjects (up to 20%), these differences were not considered to be of clinical relevance as the 90% confidence interval for the ratio of AUCs fell within pre-specified limits (0.67 to 1.5). Mean zolmitriptan and 183C91 half-lives were around 2.5 h for both populations. Urinary excretion of the four analytes was similar in Japanese and Caucasians. Plasma concentrations of zolmitriptan were higher in Japanese females than males (AUC 40% and C(max) 29% higher), consistent with the results previously obtained in Caucasians. CONCLUSION: Pharmacokinetic parameters of zolmitriptan were similar between Caucasian and Japanese volunteers.